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NIH Research Projects · FY 2025 · 2017-09

ABSTRACT Immunotherapy (IMT) has emerged as a promising treatment strategy across a broad spectrum of human cancers, with multiple agents, particularly immune check point inhibitors, showing promising results in various types of cancers. Its full potential has yet to be realized, due in part, to a lack of biomarkers predicting response to treatment. Multiple immune and genomic biomarkers of response based on analysis of pre-treatment specimens have been described but most are not very robust with significant overlap between responders and non-responders. Therefore, there is a critical unmet need to perform comprehensive characterization of candidate biomarkers in early phase IMT trials using standardized assays and novel methodologies. Recognizing the need for comprehensive immune monitoring for IMT clinical trials, in 2017 NCI developed the Cancer Immune Monitoring and Analysis Center (CIMAC) and Cancer Immunologic Data Commons (CIDC) Network, with the goal of identifying biomarkers of response, resistance, and adverse events to optimize immunotherapy approaches for patients with cancer. The MD Anderson Cancer Immune Monitoring and Analysis Center (MDA-CIMAC) is one of four CIMAC sites established five years ago that has been standardizing genomic, pathology and immunology assays and supporting profiling of tissue and blood specimens from patients treated in IMT trials. The MDA-CIMAC will be co-led by Drs. Ignacio Wistuba, renowned cancer surgical and molecular pathologist, Gheath Al-Atrash, well-known medical oncologist with expertise in stem cell transplantation and immunotherapy, and Cara Haymaker, cancer immunologist with expertise in immune biomarker analysis. They will be supported by a multidisciplinary team of world-class and highly collaborative experts on cancer and immunotherapy. The main goals of MDA-CIMAC are to: 1) provide a centralized and harmonized platform for sample collection, processing and quality assurance, and 2) use analytically-validated and standardized (Tiers 1 and 2) and highly innovative (Tier 3) assays to offer analyses for phenotypic, genomic, and functional characterization of responses of patients enrolled on IMT clinical trials. In Aim 1, we will utilize Standard Operating Procedures (SOPs) following the developed CIMAC umbrella protocol to provide services for processing and distribution of annotated biospecimens from the NCI-sponsored early phase immunotherapy clinical trials and to link the specimens to relevant clinical, pathological, immune and molecular data within the CIMAC-CIDC Network. In Aim 2, we will perform routine and innovative pathological, immunological and molecular analyses using standardized and validated and highly innovative assays to aid the completion of NCI- sponsored early phase clinical trials and the development of novel predictive IMT biomarkers. In Aim 3, in conjunction with the CIDC team, we will provide biostatistics and computational services for data collection and analysis, and will perform, interpret and predict modeling of high dimensional (‘omic”) data. We envision that the MDA-CIMAC will be indispensable as we make meaningful progress in cancer immunotherapeutic approaches.

NIH Research Projects · FY 2025 · 2017-09

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Project Summary The objective of the proposed program renewal is to develop capacity of biomedical research trainees and their commitment to research careers by providing their mentors with linguistically informed and evidence-based knowledge, skills, and resources for mentoring scientific communication (SciComm). “SCOARE 2.0” builds on the existing program “Scientific Communication Advances Research Excellence” (NIH-NIGMS, R25GM125640, 2017-2022), and will expand its reach, augment its curriculum, and ensure its sustainability. Formal evaluations and preliminary research findings of the original SCOARE program suggest that providing mentors with the relevant knowledge and skills about SciComm development results in a variety of important and measurable benefits for their mentees and themselves. The specific aims of SCOARE 2.0 are to 1) Broaden availability of the existing SCOARE workshops and facilitator training; 2) Adapt the workshop for future-faculty audiences and add new modules that provide deep dives on giving quality feedback and on the use of artificial intelligence tools; 3) Increase impact and sustainability of the program by translating it to a hybrid asynchronous format. The expected outcomes for this program include continued delivery of the existing face-to-face program nationally to a minimum of 300 participants (faculty, administrators, and future faculty) as well as train approximately 80 new facilitators; development and delivery of the new content modules; development and launch of an enduring asynchronous version of the workshops, freely available online; and external evaluation of all new components. The innovation of the work is that it is grounded in linguistic and social-cognitive evidence that leverages the powerful links between language, motivation, and professional identity and that, to our knowledge, it is the first mentor training curriculum to address SciComm skill development and its deeper influence on mentee career intentions. The impact of this program will be to help mentors build a research workforce possessing superior training and high professional commitment, thus aligning with the NIH’s goals providing a return on its investment. The investigators are ideally positioned to carry out this project because of their experience collaborating on the design, delivery, and evaluation of the existing SCOARE program.

NIH Research Projects · FY 2026 · 2017-08

Molecular Determinants of Synaptic Plasticity in Chronic Pain The long-term goal of our project is to identify the molecular and signaling mechanisms that govern synaptic plasticity under chronic pain conditions. Neuropathic pain remains a major therapeutic challenge, and neuronal plasticity at the spinal cord level is fundamentally important to the development of chronic neuropathic pain. N- methyl-D-aspartate receptors (NMDARs) are expressed in primary sensory neurons and their central terminals in the spinal dorsal horn. However, they are functionally inactive under normal conditions and become tonically activated to potentiate glutamatergic input to spinal dorsal horn neurons after nerve injury and chemotherapy- induced neuropathy. The molecular mechanisms regulating the synaptic activity and trafficking of NMDARs in the spinal dorsal horn remain poorly understood. Volume-regulated anion channels, which are formed by multiple different leucine-rich repeat-containing protein 8 (LRRC8) family members, are crucial to the regulation of cell volume. In our pilot studies, we found that LRRC8A was highly expressed in dorsal root ganglion (DRG) neurons. Also, traumatic nerve injury selectively downregulated LRRC8A, but not LRRC8B-LRRC8D, in the DRG. Furthermore, LRRC8A downregulation or conditional knockout in DRG neurons induces NMDAR-dependent pain hypersensitivity. Importantly, we discovered that LRRC8A physically interacted with NMDARs to control synaptic trafficking and activity of NMDARs. In this renewal application, we will specifically determine the roles of LRRC8A in the regulation of nociception and synaptic NMDARs at the spinal cord level in two neuropathic pain models. On the basis of our intriguing preliminary data, we propose to test the overall hypothesis that LRRC8A protein directly interacts with NMDARs and normally restrains the synaptic trafficking of NMDARs at the spinal cord level; nerve injury or chemotherapy diminishes LRRC8A expression and augments the synaptic expression and activity of NMDARs, leading to increased glutamatergic input to spinal dorsal horn neurons and chronic pain. We will apply several innovative and complementary approaches, including biochemical and cellular analyses, transgenic mice, and synaptic recordings to study how LRRC8A controls NMDARs and nociception at molecular, cellular, and behavioral levels. Our project will generate fundamental new information about the molecular basis of NMDAR-mediated synaptic plasticity in neuropathic pain. Findings from our project are expected to advance our knowledge of molecular mechanisms of nociceptive regulation and to guide the development of new strategies for treating chronic neuropathic pain.

NIH Research Projects · FY 2026 · 2017-08

PROJECT SUMMARY: OVERALL COMPONENT This application is a competing renewal of the “Specific Pathogen Free 18 Baboon Research Resource” (SPF18BRR) P40 OD024628. The SPF18BRR was founded with NIH support at the University of Oklahoma Health Sciences Center (OUHSC) in 2002 and was relocated to the Keeling Center in 2017. The SPF18BRR has received continuous NIH support since it was founded. The SPF18BRR is the only national research resource of adventitious virus free olive baboons (Papio anubis) that are available to NIH grantees; intramural research programs of federal agencies, including the FDA, NSF and NIH; and other sponsors of biomedical research (private foundations, pharmaceutical companies, and contract research organizations). Absolutely unique in the entire world, the baboons in the SPF18BRR have an extensive bioexclusion list of 18 pathogens normally found in other wild and captive nonhuman primate colonies. The SPF18BRR has integrated multiple disciplines into a program designed to meet the needs of investigators who utilize its resources. During the proposed period of support, the SPF18BRR will continue to improve the resources it provides to users and will continue to add new information about the biology and research value of virus free baboons to its website. Baboons continue to be important animal model for genetically engineered pig xenotransplantation, are the only NHP model of respiratory syncytial virus and whooping cough, and they remain a very important model of bacterial sepsis. Additionally, baboons are excellent models of human COVID associated pneumonia, and they were instrumental in the development of approved vaccines for SARS CoV-2. Over the next five years, the SPF18BRR will focus on expanding the SPF18 baboon breeding colony to meet current and future biomedical research needs. The aims of the Resource Core Component address our continued commitment to expanding the SPF18 baboon breeding colony, we will increase the genetic diversity of the SPF18 breeding colony, and we will provide SPF18 baboons, facilities, training, and expertise to the scientific community. The Applied Research Component will include projects to develop methods to train and collect data from automated cognitive testing systems in socially living baboons; we will also determine a DNA methylation clock for our baboon colony, and will perform baseline biomarker analysis for a panel of 30 biomarkers for all animals over 3 years old in our colony; and, we will perform whole genome sequencing on 9 future conventional baboon breeders from the Southwest National Primate Center’s olive baboon colony, as well as targeted genomic sequencing on other interesting animals from the SPF18BRR. The overall goals of theSPF18BRR are to provide a national research resource of virus free olive baboons; provide baboon derived biological materials; provide education and training opportunities to scientist, colony managers, and animal caregivers who want to work with baboons; and to provide investigators with facilities and expertise to conduct studies using virus free baboons.

NIH Research Projects · FY 2024 · 2017-07

ABSTRACT The principal goal of this competitive renewal is to establish clinical brain tumor perfusion imaging protocols strategically designed for high accuracy, physiologic sensitivity and clinical applicability. Dynamic susceptibility contrast (DSC) MRI is one of the most widely used advanced imaging techniques in neuro-oncology, with a reported use of 85% in all routine brain tumor scans at sites across the US and Europe. During the previous funding cycle, the singular aim of the project was to identify the most accurate DSC-MRI acquisition protocol(s) by developing, validating and applying a population-based digital reference object (DRO) and then verifying these protocols in patients with brain tumors. The most significant finding of this effort was the identification and clinical validation of an accurate single contrast agent dose and single-echo DSC-MRI protocol, which has now been adopted as the consensus recommendation by the brain tumor imaging community. Another key result of this project was the validation, using the DRO and a prospective patient study, of a single-dose, dual-echo DSC- MRI sequence, an approach that enables simultaneous assessment of DSC and dynamic contrast enhanced (DCE)-MRI data, as the protocol with highest accuracy, even across variable pulse sequence parameters and tissue properties. Building on the success of this prior work, we now aim to overcome two obstacles that still limit DSC-MRI’s clinical utility, accuracy, and multi-site consistency: i) a reliance on echo planar imaging (EPI) based pulse sequences that undermine the geometric fidelity, reliable colocalization of perfusion and anatomic images and accuracy of derived DCE-MRI data, and ii) lack of validation of, and a benchmark for, brain tumor DSC/DCE- MRI post-processing algorithms and software, for both single- and dual-echo acquisitions. These limitations represent critical and clinically relevant challenges that urgently need to be addressed. To address these issues, we propose to: 1) establish an anthropomorphic benchmark for validating brain tumor DSC DCE-MRI analysis tools and 2) develop a three-dimensional, dual-echo pulse sequence for simultaneous DSC/DCE MRI. In this project we will provide the neuro-oncology community with validated image acquisition and analysis methods for accurate, physiologic sensitive and clinically applicable DSC/DCE-MRI mapping methods in brain tumor patients. We will provide the first DSC/DCE-MRI anthropomorphic benchmark that can be used to validate existing and future algorithms and software, thereby improving multi-site and clinical trial consistency. Ultimately, validated DSC-MRI techniques will improve its reliability and relevancy across a range of clinical scenarios, including tumor localization, therapy response assessment, surgical and biopsy guidance, and multi-site clinical trials of conventional and targeted brain tumor therapies.

NIH Research Projects · FY 2026 · 2017-03

Signaling Mechanisms of Opioid-induced Hyperalgesia and Tolerance Project Summary The major objective of this project is to identify key signaling mechanisms responsible for the development of opioid-induced hyperalgesia and analgesic tolerance (OHT). Opioid drugs remain indispensable for treating severe pain caused by surgery, trauma, and cancer. However, acute and repeated administration of μ-opioid receptor (MOR) agonists often cause OHT, the major obstacle to adequate pain relief with opioids. OHT can also lead to unsafe opioid dose escalation, resulting in dependence, addiction, and even overdose death. Opioid signaling is complex and has been studied mostly in vitro, but the functional significance and relevance of various opioid signaling components to OHT are poorly understood. N-methyl-D-aspartate receptors (NMDARs) are a clinically validated target for treating OHT, and extracellular signal-regulated kinase (ERK) is stimulated by MOR activation and is involved in opioid-induced NMDAR hyperactivity at the spinal cord level and in OHT. At present, little is known about the upstream signaling mechanism leading to stimulation of ERK at the spinal cord level during OHT. Although BRAF, a serine/threonine-specific protein kinase, is a crucial upstream signal for ERK activation, its role in OHT has not been recognized previously. In our preliminary studies, we found that repeated treatment with opioids increased BRAF activity in the spinal cord. Furthermore, BRAF inhibition or knockdown at the spinal cord level substantially attenuated OHT and rescued the synaptic trafficking and expression of MORs and NMDARs in the spinal cord altered by opioid treatment. These initial findings suggest that BRAF- dependent signaling plays a key role in the control of synaptic MOR and NMDAR plasticity in the development of OHT. Therefore, in this competing renewal application, we will test the overall hypothesis that repeated treatment with opioids, through the BRAF-mediated signaling axis, induces (1) analgesic tolerance by inhibiting expression and activity of MORs at primary afferent central terminals and (2) hyperalgesia by promoting trafficking and activity of NMDARs at primary afferent terminals synapsing with spinal cord excitatory neurons. To test this hypothesis, we will use a multidisciplinary approach, including protein biochemistry, electrophysiological recordings in spinal cord slices, and targeted gene knockout and knockin. Our proposed studies are expected to advance our understanding of the fundamental signaling mechanisms highly relevant to the development of OHT. Our project also has important clinical implications and could lead to new strategies (e.g., using FDA-approved BRAF inhibitors) for improving opioid analgesic efficacy in patients with severe pain.

NIH Research Projects · FY 2025 · 2016-08

DESCRIPTION Ovarian clear-cell carcinoma (OCCC) is the second most common type of ovarian cancer and is associated with poor survival because of the lack of effective therapeutic options. Our long-term goal is to understand the molecular mechanisms that create therapeutic opportunities in OCCC and to translate such discoveries into meaningful clinical applications. ARID1A, a component of the chromatin remodeling complex SWI/SNF, is mutated in more than 50% of OCCC. With the support of our current R01 project, we have established a successful research program to study the role of the ARID1A-SWI/SNF complex in regulating the DNA damage response (DDR) and DNA repair. In the preliminary studies leading to this renewal application, we discovered a new role for the ARID1A-SWI/SNF complex in transcriptional silencing of heterochromatin repetitive DNA sequences, namely satellite DNA element (satDNA) in response to ionizing radiation (IR)-induced DNA damage. We also showed that aberrant IR-induced satRNA expression activates RNA-sensing innate immune response in ARID1A-deficient cells. These exciting and promising findings have led us to hypothesize that ARID1A deficiency unleashes IR- induced de-repression of heterochromatin repetitive satDNA sequences by impairing DNMT3A-mediated DNA methylation and transcriptional silencing. This consequently activates the dsRNA-sensing RIG-1/MDA5 pathway, and provides the rationale to use ATM inhibitors to enhance the efficacy of radiotherapy and immunotherapy by selectively modulating nucleic acid-mediated innate immune response in ARID1A-deficient tumors. We will employ multidisciplinary approaches, including molecular/biochemistry/cell biology-based mechanistic studies, shRNA/CRISPR-Cas9-based genetic studies, bioinformatic analysis and preclinical animal model-based translational studies, and analysis of OCCC patient samples to test this hypothesis. Together, our proposed project will not only mechanistically advance our fundamental understanding of the underlying biology of how the ARID1A-SWI/SNF chromatin remodeling complex maintains heterochromatin transcriptional silencing to radiation-induced DNA damage, but will also develop new personalized immune- based radiotherapy regimens tailored to the genetic contexts of tumors, such as ARID1A deficiency or more broadly SWI/SNF-mutated cancers.

NIH Research Projects · FY 2026 · 2016-08

ABSTRACT Follicular lymphoma (FL) is an indolent but incurable malignancy of germinal center B (GCB)-cells, and is the second most common form of non-Hodgkin lymphoma (NHL). Mutations of CREBBP, which encodes a lysine acetyltransferase (KAT) protein, occur in ~60% of FL and arise early during disease evolution. We found that conditional knock-out (KO) of Crebbp in murine models and can cooperate with Bcl2 over-expression to drive B- cell lymphoma, but that these tumors had key differences to FL. Furthermore, FL tumors have a predominance of missense mutations within the CREBBP KAT domain and infrequently harbor nonsense/frameshift mutations that are modeled by KO. We therefore modeled the most frequent CREBBP KAT domain mutation, R1446C, using CRISPR editing of a CREBBP wild-type (WT) lymphoma cell line and found that CREBBP-R1446C mutation has a more profound epigenetic effect than biallelic knock-out (KO). Regions with reduced H3K27Ac were enriched for loci that are normally bound by both CREBBP and BCL6 in germinal center B-cells, suggesting that the loss H3K27Ac may be linked to failure of CREBBP to oppose BCL6-dependent HDAC3 activity. Notably, BCL6 also recruits EZH2 and loss of H3K27Ac in CREBBP-R1446C cells was accompanied by a gain of the EZH2-catalyzed H3K27me3 mark, suggesting that enhancer inactivation via loss of H3K27Ac is followed by enhancer decommissioning through addition of H3K27me3. Furthermore, the CREBBP mutation phenotype could be partially rescued by either HDAC3 or EZH2 inhibition, and was further enhanced by combination of HDAC3 and EZH2 inhibitors. These results suggest that CREBBP KAT domain mutations suppress histone acetylation through a dominant repressive mechanism, and that epigenetic crosstalk between CREBBP and EZH2 may play a prominent role in regulating the epigenetic landscape of B-cell lymphoma. We have extended upon these observations by performing biochemical and structural analysis of major CREBBP mutational hotspots and observed key differences between the R1446C/H alleles and the next most common hotspots at Y1482 and Y1503. These amino acids all reside within the catalytic pocket of CREBBP, but R1446 mediates interaction with the CoA portion of the acetyl donor, acetyl-CoA, while Y1482 and Y1503 mediate interaction with the acetyl group. While R1446 mutations maintain some catalytic activity, the Y1482 and Y1503 mutations are catalytically dead. Therefore, these mutations are likely to have different functional consequences. In this proposal, we aim to (i) characterize the mechanism of dominant epigenetic repression by CREBBP KAT domain mutations and differences in function between KAT domain hotspot mutations, and (ii) define the role of epigenetic crosstalk between CREBBP and EZH2 in B-cell lymphoma, and the consequences for response to targeted agents.

NIH Research Projects · FY 2026 · 2016-08

Project Summary PTEN (phosphatase and tensin homolog) is among the most commonly altered tumor suppressor genes in human cancers. The overarching premise of this project is twofold. First, while PTEN function can be compromised by genetic mutations in inherited syndromes and sporadic cancers, post-translational modifications (PTMs) of PTEN may play key roles in the dynamic regulation of PTEN function. Prior studies on PTEN PTMs, including our work supported by this award, identified that deregulated ubiquitination and deubiquitination lead to detrimental effects on PTEN stability and subcellular localization, thereby causing tumorigenesis. Secondly, PTEN fulfils many of its tumor suppressive roles through the PI3K-AKT-mTOR pathway; however, the role of PTEN has also been shown to extend beyond the control of PI3K, with PTEN implicated in controlling genomic stability and cell cycle progression, although the mechanism remains unclear. The overall goal of this application is to investigate the mechanisms of nuclear PTEN-mediated tumor suppression, focusing on cancer-specific PTM regulation of PTEN compartmentalization and non-canonical functions independent of its cytoplasmic phosphatase activity. Our new preliminary study revealed the novel upstream PTM mechanism and essential downstream effectors for nuclear PTEN in cancer. Multi-omics analyses of proteome, transcriptome and epigenome revealed a clear link between the PTEN-chromatin remodeling factor axis and genomic integrity within the nucleus. Further, this novel PTEN-associated chromatin remodeling factor conferred synthetic essentiality in cancer cells lacking nuclear PTEN. Based on these observations, we hypothesize that canonical and non-canonical PTEN signaling coordinately reduces tumorigenesis and therapy resistance. To test this hypothesis, we will (1) determine how PTEN PTMs occur and their role in cancer; (2) define the non-canonical roles of PTEN in tumorigenesis and genomic instability; (3) explore the therapeutic potential of the PTEN-chromatin remodeling factor axis in cancer. The completion of this project will not only gain insight into the molecular and cellular mechanisms by which the newly characterized PTM of PTEN tipping the balance between its canonical and non-canonical signaling, but also yield critical information about the development of effective strategies for precision treatment of PTEN loss-of- function driven cancers.

NIH Research Projects · FY 2026 · 2016-07

PROJECT SUMMARY Small cell lung cancer (SCLC) is a highly aggressive disease for which there remains a critical need for therapies that provide durable benefit and biomarkers to guide treatment selection. While immunotherapy provides clinical benefit for some patients, overall survival with current chemotherapy-immunotherapy combinations in unselected patient populations remains only ~12 months. A particularly understudied feature of SCLC is therapeutic approaches to enhance immune-mediated responses for this largely immune “cold” cancer. Our group has previously identified promising drug targets, strategies to enhance immunotherapy response, and candidate predictive biomarkers for SCLC (including PARP and other DNA damage response inhibitors alone an in combination with immunotherapy). These have been rapidly translated into clinical trials. To address current research gaps (outlined in the NCI’s SCLC Progress Working Group report), including (1) investigation of the SCLC microenvironment (including the potential and limitations of immunotherapy), (2) tumor heterogeneity, (3) characterization of longitudinal patient samples, (4) models of newly identified subtypes, and (5) development of blood-based biomarker approaches, we have assembled a multidisciplinary team with scientific, clinical, translational, and computational expertise in the field of SCLC and cancer immunology. Together with our Thoracic Bioinformatics Working Group, we recently found that there are four distinct, expression-based molecular subsets of SCLC, including a novel “Inflamed” subtype (Gay et al, Cancer Cell, 2021). Importantly, these SCLC subtypes (SCLC-ASCLC, NEUROD1, POU2F3, and SCLC-Inflamed) have distinct therapeutic vulnerabilities that can be leveraged to enhance response to ICB combinations. We have generated and profiled new patient-derived xenograft models from biopsies and circulating tumor cells (“CDXs”) representing the major SCLC subtypes. These, together with an established humanized mouse model system, will enable us to deeply characterize mechanisms of immune response to combinations of ICB and DNA damaging therapies. Based on our data, we hypothesize that SCLC subtypes and SLFN11 status will determine distinct, immune mediated responses to DNA damaging therapies and ICB and that novel combinations targeting replication stress may enhance ICB response in immune “cold” SCLC. To address these hypotheses, in Aim 1, we will determine the SCLC molecular subtype-specific immune modulatory effects of DNA damaging therapy in co-clinical trials in vivo and in patient specimens before and after treatment. In Aim 2, we will investigate cancer cell SLFN11 as a predictive biomarker and its role in STING pathway activation and anti-tumor immunity. Lastly, in Aim 3, we will assess methods to overcome resistance, including alternative DNA damaging agents combined with ICB. The overall hypothesis is that molecular subtyping of SCLC tumors, paired with strategies to enhance immunotherapy response, will improve survival for patients with SCLC by providing a personalized, biomarker-informed approach to therapy.

NIH Research Projects · FY 2026 · 2016-06

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related death in the United States. To address the magnitude of this problem, it is critically important to identify those at high risk for HCC and institute effective surveillance strategies for early diagnosis. Liver cirrhosis is the main risk factor for HCC. Bi- annual ultrasound and α-fetoprotein remains the surveillance modality most frequently used in patients with cirrhosis, despite very low sensitivity and specificity. Our goals are to identify a blood-based model for risk stratification in patients with cirrhosis, as well as an integrated blood-based and liver imaging model to optimize early HCC detection in high-risk patients. During the first grant period, we developed a multi-center prospective cohort of patients with cirrhosis under contrast MRI surveillance. Such cohort provides a unique opportunity to study blood biomarkers and imaging features on clinical material from patients rigorously classified as having a very early disease in a surveillance setting. Longitudinal collection of paired blood samples and MRIs from these patients is particularly valuable in assessing how early blood markers and imaging features become positive during the period when lesions are observed to obtain a diagnosis of HCC. To date, 912 cirrhotic patients have been enrolled and 2590 paired blood samples and MRIs have been collected. During follow-up, 63 patients developed HCC and 212 patients had detectable lesion(s). In parallel, we have identified in plasma and exosomes, proteins and metabolites for HCC risk prediction and early detection. We also developed quantitative imaging and artificial intelligence (AI)-based methods to analyze imaging scans of patients with liver cancers. We demonstrated how voxel-wise enhancement pattern mapping (EPM) can improve the contrast-to-noise ratio in CT scans. We extended this finding to MRIs for patients with HCC, including patients in our prospective cohort. Differences in EPM signals from pre- diagnostic MRIs to diagnostic MRIs may improve early detection and lesion characterization. Our AI-based tools complement the EPM algorithm by providing high-throughput tools to process the thousands of MRIs from our patient cohort in an efficient and accurate manner. In this competing renewal, we will extend the existing cohort and further evaluate the performance of these novel blood and liver MRI markers. We will determine longitudinal changes and evaluate their capacity to detect preclinical disease. We will identify the panel of markers that best predict HCC development and that could therefore have utility in risk assessment and early detection of HCC. This proposal achieves in one study two major goals: i) early detection and ii) characterization of tumors when biomarker becomes positive. The impact is multiple: spare patients from unnecessary imaging tests; identify high-risk patients and trigger the decision to perform MRI for surveillance instead of ultrasound; detect lesions at an early stage allowing for curative treatment. Together, these clinical applications would significantly reduce the cost of HCC surveillance and improve survival of HCC patients.

NIH Research Projects · FY 2026 · 2016-05

ABSTRACT: Advances in cytoreductive surgery and combination chemotherapy have improved 5-year survival in patients with epithelial ovarian cancer, but the rate of cure remains essentially unchanged over the last two decades. Computer models suggest that detection of ovarian cancer in early stage (I-II) could improve rates of cure by 10-30%. In two major trials, a two-stage strategy where rising values of CA125 analyzed with a Bayesian Risk of Ovarian Cancer Algorithm (ROCA) prompted transvaginal sonography and abnormal imaging prompted surgery proved sufficiently specific to exceed a positive predictive value (PPV) of 10%. With support of the EDRN, 7,869 apparently healthy women have participated in the Normal Risk Ovarian Cancer Screening Study (NROSS) at 11 different sites in the United States with 46,008 CA125 determinations over the last 21 years. Twenty-nine patients have been referred for operations detecting 17 ovarian cancers with 12 (71%) in early stage I or II. In addition, 4 cases of early stage endometrial cancer were detected, yielding a PPV for detecting cancer of 72%. No more than 2-3 operations will be required to detect each case of ovarian cancer. As CA125 is expressed by only 80% of epithelial ovarian cancers, better sensitivity is likely to be achieved with multiple biomarkers. During this grant cycle we have reported that HE4, HE4 antigen-autoantibody complexes, and osteopontin significantly enhance the sensitivity of CA125 for detecting early stage (I-II) disease and have developed a ROCA2 that includes all 4 biomarkers and detects advanced disease 1.4 to 4.8 years earlier than ROCA. We have found elevated levels of anti-TP53 autoantibodies (AA) in 20-25% of patients with ovarian cancer. Titers of anti-TP53 rise 12 months prior to CA125 and 22 months prior to diagnosis in patients where CA125 does not increase. In an EDRN consortium with investigators from Fred Hutchinson Cancer Center, Arizona State University and the Massachusetts General Hospital, we have compared 5 anti-TP53 autoantibody assays and found the RAPID assay most sensitive. Some 28 different AA have been assayed in a standard panel of 952 sera to identify three - TP53, CTAG1, and IL-8 – that can be detected in early stage disease and complement CA125. Over the last two decades, we have collected and preserved 922 blood and 774 tissue samples at the time of initial surgery in patients with ovarian cancers. During the last 6.5 years we have banked 18,754 new serum and plasma samples from the NROSS and provided serum/plasma samples for 11 investigators to test biomarkers for early stage ovarian cancer. We have published 23 peer reviewed articles, reviews and commentaries. A team of 36 investigators and staff will pursue 3 Specific Aims: 1) to conduct the NROSS2 trial to determine the specificity and PPV of a two-stage ovarian cancer screening strategy using a 4 biomarker ROCA2 and a panel of 3 autoantibodies; 2) to evaluate multiple biomarkers for early detection of recurrence or persistence of disease at positive second look operations; and 3) to maintain and share a serum and plasma bank to facilitate evaluation of novel biomarkers for early detection of ovarian cancer.

NIH Research Projects · FY 2026 · 2015-12

Project Summary ARID1A, encoding a subunit of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator across human cancers. Most notably, inactivating mutations in ARID1A occur in ~50% of ovarian clear cell carcinomas (OCCC) and ~30% of ovarian endometrioid carcinomas (OEC). There is an unmet need for effective treatment modalities for ARID1A-mutated ovarian cancers. For example, OCCC is generally refractory to standard agents used to treat epithelial ovarian cancer, and when diagnosed in advanced stages, OCCC carries the worst prognosis of all ovarian cancer subtypes. The overall goal of this proposal is to develop a novel therapeutic strategy for ARID1A-mutated ovarian cancers by targeting the IRE1a/XBP1 pathway of the endoplasmic reticulum (ER) stress response alone or in combination with an immune checkpoint blockade. We show that the ARID1A inactivation creates a dependence on the IRE1a/XBP1 pathway. We also show that ARID1A inactivation sensitizes ovarian cancer to anti-PD-L1 treatment. The objectives of this application are to investigate the mechanisms underlying the dependence on the IRE1a/XBP1 pathway created by ARID1A inactivation and to investigate novel IRE1a/XBP1 inhibition-based therapeutic strategies for ARID1A-mutated ovarian cancer. Our central hypothesis is that ARID1A-mutated ovarian cancers can be treated and ultimately eradicated by targeting the IRE1a/XBP1 pathway of the ER stress response alone or in combination with immune checkpoint blockade. Two Specific Aims are proposed: Aim 1 is to investigate the mechanism by which ARID1A-mutated ovarian cancer cells are selectively sensitive to the inhibition of the IRE1a/XBP1 pathway; and Aim 2 will target the IRE1a/XBP1 pathway for developing novel therapeutic strategies for ARID1A mutation. The proposed studies are highly innovative because they challenge current research/clinical paradigms and utilize innovative methods to explore new intervention strategies for ARID1A-mutated ovarian cancers. The research proposed is of high impact because it will provide a scientific rationale for developing urgently needed novel therapeutic strategies by targeting the IRE1a/XBP1 pathway of the ER stress response alone or in combination with an immune checkpoint blockade for ARID1A-mutated ovarian cancer, a disease that currently has no effective therapy. Since ARID1A is the most frequently mutated epigenetic regulator across human cancers, the mechanistic insights gained from the current studies will have broad implications for many different types of cancers as well.

NIH Research Projects · FY 2025 · 2015-09

Project Summary Research in the treatment for diseases of the exocrine pancreas, including chronic pancreatitis (CP), pancreatogenic diabetes mellitus (DM), and pancreatic ductal adenocarcinoma (PDAC), has been hampered by disease heterogeneity, the lack of systematically collected clinical outcome measures in longitudinal studies linked with biospecimens, and slow pace in biomarker and therapeutic development. Given the increasing incidence and prevalence of CP and its association to PDAC, its complications, high mortality rate, and associated healthcare cost, the NIH established in 2015 a consortium for the study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer as multidisciplinary teams to undertake a comprehensive clinical, epidemiological, and biological characterization of patients with CP (including recurrent acute pancreatitis) to develop treatments and biomarker tests, and gain insight into the pathophysiology of CP and its sequela: chronic pain, pancreatic exocrine and endocrine insufficiency, diabetes and pancreatic cancer association. In the last nine years, the Coordination and Data Management Center (Center) of the Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer (Consortium) has provided critical administrative, regulatory, managerial, logistic, analytic, and financial functions for the consortium, enabling the successful launch of four multicenter studies (i.e., PROCEED, INSPPIRE 2, NOD, DETECT) that aim to understand the relationship between CP, DM, and PDAC, and to better define and characterize Type 3c diabetes. In the next five years, the consortium will be renamed the Chronic Pancreatitis Clinical Research Consortium (CPCRC), and the Center will be renamed the Data Coordinating Center (DCC) to reflect the revised research focus on CP, both in children and adults and to pursue and expand the objectives of the former consortium in these areas. The DCC will further refine, optimize and innovate its time-tested infrastructure, operation procedures, and organizational structure to provide strong and continued support for the CPCRC’s studies. Specifically, we aim to (1) provide operation and coordination support; (2) continue the accrual and follow-up for the two ongoing longitudinal cohort studies, PROCEED and INSPPIRE 2; (3) support the infrastructure for biomarker development and therapeutic trials, and manage the CPCRC biobank to process, safeguard and distribute the study biospecimens for the conduct of studies approved by the CPCRC; and (4) design and support new studies selected by the CPCRC.

NIH Research Projects · FY 2026 · 2015-09

There has been a substantial growth in nanotechnology research in cancer demonstrating that nanotechnology could provide unique and otherwise unattainable solutions to cancer management including very early cancer detection, accurate molecular specific diagnosis and treatment that diminishes side effects. However, achieving this promise is extremely challenging because it requires overcoming multiple constraints imposed by translational barriers in clinical applications of nanomaterials that is multiplied by complexity of cancer biology. Currently, there is a growing gap between new discoveries coming at a fast pace from academic labs and their translation into clinic. Therefore, there is an urgent need in addressing this gap in cancer nanotechnology translational pipeline. To this end, we have designed a novel training program to educate future leaders in the broad field of nanotechnology with specific interests in cancer-related applications, who are keenly aware of the needs and demands of clinical environment as well as of major challenges of translational research. We believe that the only way to train cancer translation minded Ph.D. researchers is to insert them into the environment of an outstanding cancer center. Therefore, our program is based on a close collaboration between The University of Texas MD Anderson Cancer Center and Rice University. Our training program includes multidisciplinary mentorship of translational research projects combined with multidisciplinary, hands-on coursework and seminar experiences. All trainees will work with at least two program faculty mentors (one from Rice and one from MD Anderson) to define and carry out an independent research problem. Didactic coursework will prepare them to contribute to research projects that directly address barriers to translation of nanotechnology-based approaches and to develop the skills needed to define and lead such projects. Incoming trainees will participate in a unique one-week-long boot camp in “Cancer Management and Nanotechnology” that provides an overview of current opportunities and barriers in the field. Trainees will develop foundational background in the field from program specific seminar series and by taking courses related to translational cancer or nanotechnology topics. Trainees will gain essential writing skills through scientific writing seminars and by writing a NIH grant proposal that will be reviewed by a NIH-style Mock Study Section. Finally, trainees will gain important lab management skills by participating in a short hands-on course providing an introduction to laboratory and project management. At the end of the program, fellows will have a deep understanding of translational research in cancer nanotechnology, with the most important component being the demonstrated ability to carry out independent translational research in this challenging multidisciplinary field.

NIH Research Projects · FY 2025 · 2015-07

Project Summary/ Abstract Survival outcomes for patients with osteosarcoma have not changed since the advent of modern chemotherapy four decades ago and it has been challenging to develop new effective therapies in this disease. Our lab’s long- term mission is to identify novel molecular targets in osteosarcoma via comprehensive genomic and proteomic profiling of patient-derived cell lines and xenografts as well as human tumors with the ultimate goal of identifying and/or developing and testing therapeutics against these targets. To achieve this goal, we have a) built a robust profiling platform to identify novel targets; b) expanded our repertoire of osteosarcoma patient derived xenograft (PDX) models to reflect disease heterogeneity; and c) conducted high-throughput in vivo testing of 8-10 new agents each year both as part of Pediatric Preclinical Testing Consortium (PPTC) as well as independent of it. All of these efforts form the basis of our current research proposal and place us strongly poised to successfully achieve our goals. Our overall objective is to efficiently evaluate the efficacy of new agents with high potential to have activity in osteosarcoma based on target data from our genomic and proteomic profiling both as single agents and in rational combinations, with the vision of moving effective agents into clinical trials through the Children’s Oncology Group. We have three specific aims- 1) to select and test agents in vivo against surface targets identified by comprehensive proteomic profiling of osteosarcoma xenografts and patient tumors; 2) to select and test agents in vivo against targets identified by comprehensive genomic profiling of osteosarcoma xenografts and patient tumors; and 3) to perform testing of rationally combined agents based on target, toxicity and efficacy data of single agents. Agents from the PPTC pipeline will be selected based on either the proteomic target or genomic alteration being present in at least a subset of available osteosarcoma PDX models. The agent will be tested in selected cohorts of low/ high expressing protein target or present/ absent genomic alteration. In cases with multiple models with target expression, 3-5 mice per model will be used and in cases with few models available, 8-10 mice per model will be used for control and experiment groups with an overall n per arm per experiment of approximately 30 mice. Standard PPTC procedures will be used for tumor implantation and treatment. Tumor dimensions will be measured twice a week and response quantified as per standard PPTC definitions of complete response, maintained complete response, partial response, stable disease and progressive disease. For combination studies, three potential types of combinations will be considered based on efficacy and toxicity data- a) two surface protein targeted agents such as two antibody-drug conjugates; 2) two molecularly targeted agents and 3) a surface protein targeted agent and a molecularly targeted agent. Our results will guide the development of the next generation of clinical trials in osteosarcoma.

NIH Research Projects · FY 2026 · 2014-08

PROJECT SUMMARY The Department of Epigenetics and Molecular Carcinogenesis (EMC) at the University of Texas MD Anderson Cancer Center has hosted a hands-on laboratory-based Summer Program in Cancer Research (SPCR) for academically accomplished undergraduates for more than 25 years. Participating faculty members are not only committed educators but also internationally recognized experts in the fields of cancer epigenetics, genetics and genomics. The goal of the SPCR is to provide talented undergraduate students with a research project-based laboratory experience and exposure to the different disciplines working to address the causes, diagnosis, prevention, and treatment of cancer with an emphasis on epigenetic mechanisms. The overall Program objective is to promote careers in cancer research and clinical oncology, which is in line with the NCI mission to attract and train the best minds to become the next generation of cancer researchers. This goal will be accomplished through a formalized 10-week summer program in which students will undertake an individualized research project supervised by a faculty mentor. In addition to bench-side research, SPCR students will participate in a series of lectures, seminars, and discussion sessions to introduce them to core concepts in cancer biology and epigenetics. An epigenetics focused lecture series will cover “DNA methylation and Cancer,” “Histone code and Cancer,” “Artificial intelligence and bioinformatics in epigenetics research,” and “Cancer therapies targeting Epigenetic regulators,” which will be given by faculty members. “Works-in-Progress (WIP)” seminars, given by department faculty and trainees on their day-to-day research, will also be attended by the students. Discussion sessions led by WIP speakers and program directors with SPCR students immediately after these seminars will focus on the laboratory techniques utilized by the speaker, to introduce interns to methods relevant to epigenetics research. The Program incorporates several “field trip” experiences, designed to expand students’ horizons, such as a Graduate Student Research Day and a tour of the MD Anderson Keeling Center for Comparative Medicine, one of the premier non-human primate research facilities in the country and an important translational research component of MD Anderson. Students will also be exposed to career paths taken by multi-disciplinary investigators at MD Anderson through a series of presentations entitled “Career Conversations.” In preparation for a culminating Scientific Symposium, where students present their research projects to departmental faculty, trainees, and staff, interns will learn how to organize a scientific presentation, including background information, hypothesis, methods, results, and conclusions, and will hone their oral communication skills. Past programmatic evaluations demonstrate that the SPCR is an important contributor to the career development of participating students and influenced their decision and ability to pursue graduate or other training leading to careers in cancer-related research and medicine.

NIH Research Projects · FY 2025 · 2014-03

Project Summary The Texas Experimental Cancer Therapeutic Network (TEX-CTN) is comprised of the University of Texas MD Anderson Cancer Center (UT MDACC; Lead Academic Organization, LAO), the UT Health San Antonio Cancer Center (UT Health SA; Affiliate Organization, AO), the UT at Austin (UTA); Affiliate Organization, AO) and the UT Medical Branch at Galveston (UTMB; Affiliate Organization, AO). We propose to advance the development of novel therapeutics using precision oncology approaches and rationally designed clinical trials. The long-term objective is to provide the ETCTN with the joint expertise of the faculty from the four member institutions, expediting translating preclinical discoveries to the clinic, and to provide significant scientific and administrative leadership to the ETCTN. Our hypothesis for the optimal development of novel targeted agents includes testing within a molecularly profiled population, integrating pharmacodynamics markers in early clinical trials and programmatic assessment of predictors of intrinsic sensitivity/resistance and mechanisms of acquired resistance. We are proposing to achieve these goals through the following five specific aims: 1) To study, in an efficient, systematic and collaborative manner, the safety and clinical activity of new agents or hypothesis-driven novel combinations. 2) To molecularly profile tumors and patients (host tissues), to optimize selection of potentially relevant therapies based on the molecular aberrations identified in the tumor and immune environment, where appropriate. 3) To develop and validate clinically relevant of predictors and pharmacodynamic markers of response. 4) To mentor early career faculty, trainees and research personnel in the leadership, conduct, analysis, and reporting of ETCTN trials. 5) To provide scientific and administrative leadership within ETCTN. The TEX-CTN will unite four University of Texas institutions to facilitate access to novel therapies and biomarker-driven trials across the network, for patients with rare as well as common tumors, as well as patients from underserved minority populations. Our team consists of internationally recognized leaders of Phase I and II trials, multidisciplinary disease experts, interventional radiologists, translational pathologists, and diagnostic radiologists. TEX-CTN is well poised to attain a new paradigm for early experimental therapeutic clinical trials.

NIH Research Projects · FY 2024 · 2011-09

PROJECT SUMMARY/ABSTRACT We are witnessing a paradigmatic shift in the practice of medicine whereby the concept of targeting RNAs as diagnostic and therapeutic strategies are rapidly evolving. Lon noncoding RNAs (lncRNAs) are a highly heterogeneous group of non-coding transcripts that participate in the regulation of almost every stage of gene expression, as well as being involved in a variety of disease states. Dysregulation of several lncRNAs have also been implicated in progression of diabetic nephropathy (DN) and because of the tissue-specific characteristics of lncRNAs, they are considered as the next generation of biomarkers and promising therapeutic targets for DN progression In the last funding cycle, our lab provided strong evidence that lncRNATug1 is down regulated in several experimental models of DN and in patients with Type 2 diabetes (Long, et al. JCI, 2016). Importantly, conditional overexpression of Tug1 in podocytes mitigated progression of DN. We also published our findings demonstrating that Tug1-mediated renoprotection in DN is accomplished through a PGC1a-dependent mechanisms on mitochondrial function. Thus, we proposed that Tug1 serves as a novel therapeutic target in DN progression. Our work over the last five years suggests that Tug1 has two major effects on mitochondrial function: 1) Tug1 impacts mitochondrial function indirectly through a PGC1a-dependent mechanism in the nucleus, and 2) we now provide preliminary data suggesting that Tug1 is also translocated from the nucleus to mitochondria. However, the impact of mitochondrial-associated Tug1 (mitoTug1) remains unknown. We also provide preliminary data that Tug1 transcripts localized to the cytoplasm is translated into micropeptides. Several lncRNAs have been shown to hide small open reading frames (sORFs) encoding for small functional peptides termed micropeptides. Our preliminary findings suggest a direct effect of Tug1 encoded micropeptide on mitochondrial function. However, its role on mitochondrial homeostasis and progression of DN is unknown. In this application, we propose a convergent model of Tug1-mediated impact on mitochondrial remodeling in DN. Two fundamental questions will be addressed: 1) First, elucidating the subcellular distribution and function of mitochondrial-associated Tug1 (mitoTug1) on mitochondrial homeostasis and progression of DN, and 2) Second, identifying the biological and pathological role of a Tug1-encoded micropepetide on mitochondrial function and DN progression. We will describe the various techniques and strategies to study the potential role of Tug1 on mitochondrial remodeling, the challenges to these approaches, and our published and preliminary data. The successful completion of our application will place high priority on developing strategies to target Tug1 as a potential candidate in future clinical studies, and open a rich field for investigation on the interorganelle communication and mitochondrial metabolism in the pathogenesis of DN.

NIH Research Projects · FY 2024 · 2009-02

Project Summary Diabetic nephropathy represents the primary cause of end stage renal disease (ESRD) in the US, underscoring the need for innovative therapies for preventing its progression. We are interested in understanding the cellular and molecular mechanisms that govern mitochondrial dysfunction in the diabetic milieu with the expectation that understanding of these processes will expose potential disease mechanisms and therapeutic targets in diabetic nephropathy. The present proposal is based on our recent published observation, indicating that mitochondrial fragmentation is essential for prompting mitochondrial dysfunction in podocytes in the diabetic milieu. A detailed understanding of mechanisms that govern mitochondrial fission in the kidney remains incomplete and therapeutic targets based on these mechanisms do not exist. Because dynamin-related protein-1 (Drp1) plays an integral part in regulating mitochondrial fission, we have focused on investigating the role of Drp1 in mitochondrial fragmentation and progression of diabetic nephropathy. We have been guided by our recent published observations that high glucose leads to mitochondrial fragmentation by promoting Drp1 recruitment to the mitochondria. Deletion of Drp1 in db/db diabetic mice prevented mitochondrial fission and improved histological and biochemical features of advanced diabetic kidney disease. Importantly, we found that high glucose milieu triggers mitochondrial fission by phosphorylating Drp1 at serine 600 residue. Here, we propose to establish the crosstalk between phosphorylation of Drp1 and electron transport complexes (ETC) as key mediators of mitochondrial ROS (mROS) and potential therapeutic targets in diabetic nephropathy (DN). In support of our hypothesis, we have recently generated a novel diabetic knockin mutant mouse harboring a single phosphorylation deficient (serine-to-alanine) point mutation at the corresponding S600 site in the endogenous Drp1 allele (Drp1S600A). We observed that diabetic Drp1S600A mice exhibited improved key biochemical and histological features of DN. To assess the role of Drp1S600 phosphorylation on mROS, We next crossed diabetic Drp1S600A mice with mice that express a redox- sensitive green fluorescent protein biosensor (roGFP) specifically in the mitochondrial matrix (mt-roGFP) and observed that Drp1S600A mutation in diabetic mice leads to reduced mROS in podocytes in live diabetic animals. These findings provide compelling initial evidence into the unexpected role of Drp1 in a signaling cascade that regulates mROS, and represents a therapeutic target that might be useful in preventing diabetic kidney disease. Given these results and additional preliminary data presented in this application, this project will address the hypothesis that Drp1 phosphorylation dynamically interact with mitochondrial ETC to enhance mROS though a signaling network that is regulated by cardiolipin activation. The results of this study will provide important new insights into the role of mitochondrial morphology in the development of diabetic nephropathy, and may lead to novel therapeutic targets for the future treatment of diabetic kidney disease.

NIH Research Projects · FY 2025 · 2008-09

SUMMARY: OVERALL The overarching goal of this Brain Cancer SPORE renewal application is to reverse the notoriously poor outcome of patients with glioblastoma (GBM) and medulloblastoma (MB), the most common primary tumors in adults and children, respectively. This goal is achieved through a focused pursuit of our central hypothesis that an organized, multidisciplinary, integrated, flexible, and highly translational (“bench-to-bedside-and-back”) research program will lead to advances in the treatment of brain cancers. We seek to discover mechanistically diverse therapeutic strategies (including bio-therapies, targeted therapies, cellular therapies and immunotherapies) that attack intrinsic vulnerabilities of brain cancers, develop these strategies through rigorous preclinical testing, and deploy them in novel window-of-opportunity clinical trials. By pursuing this hypothesis over the past three funding cycles, we have successfully transitioned multiple agents from the bench to bedside by successfully undertaking a remarkable twelve clinical trials, including trials of Delta-24-RGD, an oncolytic virus , which we tested alone or in combination with the checkpoint inhibitor (ICI) pembrolizumab; Delta-24-RGDOX, an immune activating oncolytic viruses; bone marrow mesenchymal stem cells loaded with Delta-24; targeted therapies including BKM120, a PI3Kinase inhibitor; WP1066, a pSTAT3 inhibitor; IACS-010759, an OxPhos inhibitor; and engineered cord blood-derived Natural Killer (NK) cells. Also, in our current funding cycle we deciphered the genomic landscape of gliomas in underrepresented minority Black and Hispanic populations. Building on this exceptional track record, in this renewal we propose three fully translational projects that are specifically focused on overcoming the notoriously immunosuppressive tumor microenvironment (TME) of GBMs and MBs, and which are supported by four mission-critical Cores (Administrative, Pathology/Biorepository, Biostatistics/ Bioinformatics, Animal). Our Developmental Research and Career Enhancement Programs continue as incubators of new projects and portals for new investigators, with two of our proposed projects coming directly from these programs. The aims of our projects are: Combine Delta-24-RGD with genetically engineered NK cells, testing the hypothesis that oncolytic viruses and NK cells can shape the GBM immune TME to synergistic therapeutic effect (Aim 1): Restore phagocytosis in GBM-associated myeloid (GAMs) cells by targeting the QKI/PPARβ/RXRα (QPR) complex, testing the hypothesize that QPR agonists (bexarotene/ KD3010) can drive GAMs from an immunosuppressive to an anti-glioma state through QPR’s role in phagocytosis and antigen presentation (Aim 2); And exploit the immune consequences of U1 mutations in Sonic Hedgehog (Shh) MB, testing the hypothesis that the post transcriptional hyper-mutated state caused by a point mutation (r.3A>G) in the non-coding small nuclear RNA U1 of Shh MBs will exquisitely sensitize Shh MBs to ICIs and will provide novel antigens for the development of CAR T-cell strategies (Aim 3). Through these projects we will reverse the poor outcomes of GBM and MB and give new hope to patients with these devastating cancers.

NIH Research Projects · FY 2025 · 2007-08

Project Summary Treatment options are limited and prognosis is poor for patients with recurrent or metastatic sarcoma. Both soft tissue sarcoma and osteosarcoma most frequently metastasize to the lungs and are often resistant to cytotoxic chemotherapy. Novel treatment options such as immune therapy are urgently needed for long-term control and elimination of metastatic disease. In that regard, both T cell (CAR-T and TILs) therapy and immune checkpoint blocking therapy have advanced to clinical applications in other types of tumors. In fact, wildtype IL12-armed T (CAR- or TIL) cells is more powerful in eliminating tumors than T cells alone in both preclinical tumor model or clinical trial because IL12 polarize T cells to the Th1 phenotype, boost effector T cells, downregulate angiogenesis, remodel the extracellular matrix, and alter levels of immune-suppressive cytokines. One urgent challenge for either CAR-T or wildtype IL12-armed T cell therapy is adverse effects. The CAR-T cells causes severe cytokine release syndrome (CRS) and wildtype IL12 causes liver toxicity. To safely use IL12, the key is to target the IL12 gene and its transcribed/translated gene product to the tumor. To that end, we have invented a novel tumor-targeted IL12 gene (ttIL12 or CHP-IL12) that encodes the p35 subunit and p40-VNTANST fusion subunit. This first generation of ttIL12 received US issued patent(US9657077B2). Different from wildtype IL12, ttIL12 therapy is also more effective in reducing myeloid- derived suppressor cells (MDSC) and FoxP3Tregs. High levels of MDSC and FoxP3 expression are associated with poor survival amongst sarcoma patients. To address the adverse effect of T cells, the applicant has invented the second generation of ttIL12 therapy— cell membrane anchored ttIL12 (attIL12)-T cell therapy (PCT/US2017/055645; UTSC.P1424US.P1). Arming T cells (CAR-T, autologous T, or TILs) with this attIL12 has potential to reduce the risk of CRS because this attIL12-T cells seems no longer induce CRS cytokine expression and avoids T cells stall in lungs but rather accumulates in tumors. The safety, efficacy, and the immune mechanism of this attIL12-armed T cell therapy will be investigated in this application. This application is novel and impactful because a novel and safe T cell therapy will be investigated.

NIH Research Projects · FY 2025 · 2005-12

Overall -­ Abstract/Summary.  This multi-­disciplinary team focuses on the role of oncogenic Kras (Kras*) in pancreatic ductal adenocarcinoma  (PDAC)  with  an  emphasis  on  understanding  the  interplay  between  Kras*  cancer  cells  and  the  tumor  microenvironment (TME). Our objectives are to elucidate cancer cell intrinsic and TME mechanisms responsible  for resistance to Kras* extinction as well as to define co-­dependent circuits controlling metabolism and immunity.  Our P01 program comprises three highly interdependent projects and three essential scientific cores. Project 1  (DePinho  with  Allison)  will  continue  to  focus  on  elucidating  the  functional  basis  for  escape  from  Kras*  dependence, which includes intrinsic mechanisms as well as paracrine signaling involving myeloid populations.  These  cancer  cell-­TME  interactions  also  uncovered  the  importance  of  myeloid  cells  in  suppressing  tumor  immunity,  providing  the  basis  for  rational  development  of  novel  immunotherapy  regimens  with  truly  unprecedented anti-­tumor responses.  Project 2 (Bardeesy with Kimmelman and Cantley) has studied the role  of Kras* in driving anabolic growth of cancer cells and the importance of lysosomal degradative pathways in both  tumor cell metabolic homeostasis and immune evasion, leading to new clinical trials testing autophagy inhibition  in  PDAC.  Project  2  now  seeks  to  explore  how  specific  oncogenes/tumor  suppressors  co-­mutated  with  Kras*  influence metabolic dependencies as well as the immune composition of the TME. Project 3 (Kalluri with Ying)  brings together these two concepts of immunity and metabolism in the context of the unique stromal biology of  PDAC. Specifically, tumor immunity and metabolism are explored from the viewpoint of a novel Kras*-­induced  paracrine program involving a unique oncogenic type I collagen variant and a3b1 integrin signaling in the TME.  Project  3  also  utilizes  its  exosome  technology  platform  in  targeting  Kras*  combined  with  refined  immune  or  metabolism  regimens  emerging  from  the  other  projects.  The  close  interaction  of  each  Projects  with  various  clinical platforms, including the Immunotherapy Platform and the Parker Institute for Cancer Immunotherapy at  MD Anderson directed by Dr. James Allison (Investigator of Project 1), will constantly inform the work from this  P01 team and, vice versa, guide the clinical trials in real time. Highly innovative Cores for Pathology (Maitra),  Modeling & Experimental Therapeutics (Horner), Computation (Futreal), along with the Administrative Core will  enable the full potential of these Projects.

NIH Research Projects · FY 2025 · 2005-09

NIH Research Projects · FY 2025 · 2004-09

Increasing evidence suggests that the intestine plays an important role in sensing not only the presence of pathogens but also changes in the microbiota, which ultimately result in changes in the regulation of immune pathways and behaviors by communicating with neurons. However, the complexity of the nervous and immune systems of mammals makes it difficult to dissect the mechanisms by which the neural-gut axis communicates using bidirectional signals to control intestinal immunity. Studies in the nematode Caenorhabditis elegans show that bacterial colonization of the intestine results in the activation of the expression of innate immune genes in the gut and the activation of a neuroendocrine signal that controls pathogen avoidance. The germline also plays a key role in the neural-gut axis not only by transmitting the immunological memory to the next generation but also by communicating pathogenic cues that travel from the gut to the nervous system to control innate immunity. The long-term goal of this proposal is to elucidate the mechanism by which the neural-germline-gut axis communicates to sense pathogens and/or infection-induced physiological changes to control innate immunity at the whole animal level. Thus, we will explore the general hypothesis that the neural-germline-gut axis plays a critical role in the organismal response against bacterial pathogens by helping the nervous system integrate signals from infected sites and different tissues to coordinate the immune response. Specific genes and neurons will be studied to dissect the neural circuits that regulate immune activation in response to pathogen exposure and pathogen-induced alterations of the animal’s physiology. A genetics approach will also be used to identify neurotransmitters and endocrine signals potentially involved in the neural-immune communication that takes place between neurons and different tissues and infected sites. RELEVANCE (See instructions): The systemic control of innate immunity is critical because inflammation accounts for the major physiological, metabolic, and pathological responses to infections. We plan to continue our studies to clarify the role of the nervous system in the regulation of intestinal innate immune responses against bacterial pathogens. A better understanding of the neural-immune communication could lead to new therapeutic targets for diseases involving a deficient innate immune system.