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NIH Research Projects · FY 2024 · 2020-08

Abstract Perturbation of the p53 pathway is a common theme in most if not all human cancers. While attenuation of the pathway occurs most often through mutation or deletion of the p53 gene itself, amplification or over production of two important p53 inhibitors, MDM2 and MDM4 also occurs in a number of cancers. The research program funded by R01 CA47296 investigates the pathways of tumor suppression with emphasis on the role of Mdm2 and Mdm4 in p53 regulation and is currently in its 31st year of funding. This R50 application requests salary support for Vinod Pant, Ph.D. to continue providing research support to the program. Dr. Pant works as a non- tenure Assistant Professor in the laboratory of Dr. Guillermina Lozano, Unit Director on this application. Dr. Pant has more than 15 years of experience in cancer research and has a broad background in molecular biology, developmental biology, bio-chemistry and mouse genetics. Dr. Pant has made significant contributions to the program and has published multiple research articles in well-regarded journals. Relevant to this application, Dr. Pant is proficient in murine studies and in conducting CRISPR/Cas9 functional screens. Dr. Pant has carried out preliminary screens to identify the factors that allow cells to tolerate high levels of MDM2 which are otherwise toxic for normal cell growth. Dr. Pant is proceeding with secondary screens to further refine the results. In addition, Dr. Pant will perform genetic screens in MDM2 overexpressing liposarcoma cells to identify the vulnerabilities in these cancer cells. Identified factors will be validated by in vitro and in vivo studies and subsequently tested as therapeutic targets for potential treatment strategy. Dr. Pant's contribution is essential for successful completion of the aims of R01 CA47296 research program.

NIH Research Projects · FY 2024 · 2020-07

ABSTRACT Despite recent major advances in targeted therapy for melanoma, the nearly universal eventual acquisition of drug resistance remains a major hurdle that prevents durable gains in patient survival. To address this critical unmet need, we have recently used patient samples and model systems to identify S6K1 as a critical counter-resistance therapy target that lies at the downstream convergence point of the MAPK, CDK4/6, and PI3K pathways. Importantly, these are the primary drivers of both melanomagenesis and of known BRAF and MEK inhibitor resistance mechanisms, positing S6K1, an understudied drug target, as a potential broad-use salvage and/or frontline therapy. Our preliminary data is consistent with this hypothesis, as pharmacological S6K1 inhibition reversed MAPK inhibitor resistance in several drug and genetic contexts. Our central hypothesis is that understanding the mechanistic basis and clinical applicability of S6K1 inhibition in melanoma will allow for improved design of next-generation S6K1 inhibitors and combination therapies, as well as a deeper functional understanding of drug resistance mechanisms operating through and downstream of S6K1. Specific Aim 1 will focus on developing S6K1 as a key drug target in the contexts of both drug resistance and tumor initiation, and its clinical relevance will be interrogated in a series of clinical biopsies. Specific Aim 2 will determine the oncogenic mechanisms downstream of S6K1, with distinct focuses on its impact on cell cycle and metabolism. Overall, successful completion of this study will provide an evidential basis for S6K1 as a promising broad-use therapeutic target, with a mechanistic underpinning to further refine future designs and uses of pharmacological S6K inhibitors.

NIH Research Projects · FY 2024 · 2020-07

No abstract provided

NIH Research Projects · FY 2025 · 2020-07

Project Summary Chronic neuropathic pain (CNP) is usually caused by disease or damage involving the somatosensory nervous system, adversely affecting millions of Americans. It is difficult to treat and remains a major clinical problem. Opioids, acting through opioid receptors (ORs: MOR for µ, KOR for κ, DOR for δ, NOP for nociceptin), trigger a complex signaling system and function as powerful analgesics. However, chronic opioid treatment causes hyperalgesia/analgesic tolerance and addiction, which have resulted in an opioid epidemic in the U.S. The opioid-induced hyperalgesia /analgesic tolerance (OIH/AT) and addiction can be modulated by many factors including OR expression levels and heteromer formation with different ORs (for example, MOR-DOR) or with other receptors such as the cannabinoid receptor (CNR1). Our long-term goal is to develop new strategies to enhance opioid analgesic effects and reduce opioid consumption for treatment of CNP. REST is a major epigenetic regulator. We and others have found that overexpression (OE) of REST in the dorsal root ganglion (DRG), causing repression of the MOR gene oprm1, is linked to the onset and maintenance of CNP. Our recent studies indicate that peripheral nerve injury in fact reduces opioid analgesia via the REST corepressor G9a-mediated chromatin repression of oprm1. Further, our preliminary studies suggest that MORs in DRG neurons are essential for OIH/AT. This would suggest that the REST-MOR axis in DRG neurons is a major mechanism regulating both CNP and OIH/AT. However, although the discovery of oprm1 as a REST target using a gene-by-gene approach is useful, it is unclear whether REST regulates the impacts of opioid analgesia in CNP or in OIH/AT by controlling the expression of other ORs or CNR1 or both of these processes. Our preliminary results suggest that REST differentially regulates expression of these receptors in DRG neurons. While it causes a decrease in the expression of MOR and DOR, it causes an increase in the expression of NOP and CNR1, perhaps by repressing the expression of an inhibitor of these genes such as a miRNA. To begin to generate comprehensive insights into the role of REST in CNP, we have now developed an innovative experimental system consisting of Rest conditional knock-out (cKO) mice and REST conditional OE (cOE) mice. Preliminary results indicate that whereas DRG-specific Rest cKO mice show attenuated pain hypersensitivity after nerve injury, DRG-specific REST cOE mice exhibit pain hypersensitivity even without nerve injury. Thus, the two contrasting mouse models recapitulate the chronic pain transition and provide a robust system in which to study mechanisms governing OR expression in primary sensory neurons in CNP and in OIH/AT. Here we propose to test the central hypothesis that REST in DRG neurons is involved in regulating opioid analgesia in CNP and in OIH/AT by governing ORs/CNR1 expression through epigenomic regulation of these genes. Thus, manipulation of REST in DRG neurons could be utilized to increase opioid analgesic efficacy and reduce opioid consumption. The project is responsive to PAR-18-742.

NIH Research Projects · FY 2024 · 2020-07

PROJECT SUMMARY/ABSTRACT Tumor hypoxia predicts poor outcomes across all cancers and is a well-established source of resistance to both chemo- and radiotherapy. We have shown that T cells fail to thrive in hypoxic zones of cancer underlying the failure of checkpoint blockade for immune “cold” indications such as pancreatic and prostate cancer. While our prior work relied on our serendipitous discovery that the hypoxia-activated prodrug, TH-302, could efficiently reduce tumor hypoxia, there have been no studies to identify the most effective means to reduce hypoxia in cancer. Mechanistically, tumor hypoxia results from the combination of diminished oxygen supply coupled with enhanced tumor oxygen consumption. While each of these influences helps to foster hypoxia and nucleate an immune suppressive state, nothing is known of their relative importance in establishment of the hypoxic state itself, nor of their differential impact on tumor-infiltrating T cells within hypoxic regions. Further, we lack an understanding of the factors governing durability of hypoxia-reduction, and of any interventions to limit tumors’ capacity to restore the hypoxic state. At a deeper level, the precise molecular signals triggered by hypoxia, which reprogram myeloid and myofibroblast cells in the stroma to adapt metabolically to the hypoxic state and acquire immune suppressive function also remain unclear. We therefore hypothesize that tumor hypoxia and associated immune suppressive programming of the myeloid and myofibroblast stroma can be reduced through both local tissue remodeling and through limitation of tumor oxygen metabolism. Our first aim is to determine the kinetics of hypoxia and immune infiltrate modulation by hypoxia-activated prodrugs, oxidative phosphorylation (OxPhos) inhibitors, and anti-angiogenic agents. For each class, we will establish the kinetics by which they reduce hypoxia, how durable that reduction is post-therapy, and whether re-treatment can eliminate re-emergent hypoxia. This first of its kind systematic study will not only reveal optimal approaches for reducing tumor hypoxia in an immune-potentiating context but will also provide insights into the relative contribution of disrupted oxygen supply versus elevated tumor oxygen consumption toward establishing hypoxia. Second, we will investigate the impact of OxPhos inhibitors on both tumor and T cell metabolism and hypoxic fitness. We will assess how three inhibitors of OxPhos metabolism, which target distinct subunits of Complex I, impact tumor versus T cell metabolism, function, and hypoxic adaptation. These studies will provide critical insight into whether tumor oxygen consumption can be inhibited in a manner which compromises tumor hypoxic fitness and immune privilege without damaging the functional capacity of anti-tumor immunity. The third aim of this proposal utilizes mice lacking hypoxia-inducible factor 1-alpha (HIF1α) or HIF2α in either their tumor myeloid stroma or myofibroblasts to map the downstream signals responsible for functional and metabolic programming of these cells in response to hypoxia. These studies will provide critical insights allowing clinical hypoxia reduction to improve and with it our capacity for immunotherapy of “cold” cancers.

NIH Research Projects · FY 2025 · 2020-06

Abstract Complete removal of tumor lesions with surgical resection is the treatment of choice for patients with early stages of non-small cell lung cancer (NSCLC), as well as with many other types of cancer. It often results in cancer cure. However, substantial proportion of patients develops local or distant recurrences within several years. It is widely accepted that small numbers of tumor cells disseminate from primary tumor site early on during tumor development and persist in dormant state until cells re-enter the cell cycle. Cancer cell dormancy can also be the response to radiation and chemotherapy associated with DNA damage, which explains recurrence even after a complete response to therapies. Those dormant cells usually have characteristics of senescent cells, thus this phenomenon is often referred as “therapy-induced senescence” (TIS). Although signaling in dormant and senescent tumor cells is relatively well understood, much less is known about the mechanisms that evade dormancy to form local recurrence or distant metastases years after complete elimination of primary tumor. In this application, we model tumor cell dormancy by using two experimental systems. The first is the induction of dormancy by regulation of the expression of tumor suppressor gene p53 in lung cancer cells. This model allows for the study of tumor dormancy, which is not induced by treatment with chemo- or radiation therapy and may reflect changes in tumor cells after dissemination to tissues. The second is the model of TIS in mouse lung and human ovarian cancer treated with chemotherapy. Our preliminary studies demonstrated that neutrophils were able to induce proliferation of dormant tumor cells. We found that this effect could be caused by neuroendocrine adrenergic hormones as the result of prolonged stress. We suggest a novel concept of regulation of tumor recurrence. We propose that adrenergic hormones cause a rapid release and autocrine/paracrine signaling by S100A8/A9 proteins heterodimer leading to up-regulation of myeloperoxidase (MPO) in neutrophils. MPO and ROS contributed to formation of oxidized lipids by neutrophils, which directly activated dormant tumor cells. The main goal of this study is to identify the mechanism of recurrence in cancer and to determine therapeutic targeting strategy to control this process and ultimately eliminate dormant tumor cells to prevent recurrence. To achieve this goal, we propose the following specific aims. Specific Aim 1. To identify specific mechanisms of neutrophil-mediated reactivation of dormant tumor cells. Specific Aim 2. To determine signaling in dormant tumor cells responsible for their reactivation, to identify clinical significance and therapeutic targeting of reactivation of dormant tumor cells.

NIH Research Projects · FY 2025 · 2020-05

Invasive cervical cancer is the 4th most common cancer and cause of cancer-related mortality in women worldwide. Low- and middle-income countries (LMICs) experience almost 90% of the global cervical-cancer burden, with sub-Saharan Africa (SSA) experiencing the highest rates of cervical cancer. Human immunodeficiency virus (HIV) infection, which also disproportionately affects SSA, greatly increases the risk of cervical cancer. The World Health Organization now has a call-to-action for the elimination of cervical cancer, which includes vaccination young adolescents against human papillomavirus (HPV), the obligate viral cause of cervical cancer, and screening mid-adult women for the early detection and treatment of cervical abnormalities before becoming cancerous. However, both the best strategy for treating cervical abnormalities in women living with HIV (WLWH) from SSA and how to mitigate treatment failures are unknown. To address this gap in knowledge, we propose a randomized clinical trial to assess the treatment effectiveness of two ablative methods of treatment, gas-based cryotherapy and thermocoagulation, for treatment of CIN2/3 and high-risk HPV in WLWH women. Eligible, confirmed WLWH women (n=5,014), ages 25-49 years, and living in Maputo, Mozambique, in conjunction with the local PEPFAR (President's Emergency Plan For AIDS Relief) program, will be recruited to participate in this trial when attending their routine HIV-care visit. Consenting WLWH will be screened by rapid, point-of-care hrHPV DNA testing, unaided visual inspection after acetic acid (VIA), and “deep learning”-derived, automated visual evaluation (AVE) algorithm applied to a digital image captured on a cell phone, thereby ensuring that most CIN2/3 in the population is identified and treated. Screen-positive (HPV, VIA, 6-mo AVE positive) women will be 1) randomly assigned to either the GBC or thermocoagulation, 2) undergo a rigorous colposcopic evaluation and biopsies to determine the (post-hoc) diagnosis of the cervical abnormality, and 3) undergo their assigned treatment if ablation eligibility or LEEP if ineligible based on WHO guidelines8. Adverse events and pain data will be collected systematically during the treatment visit and during an at-home, one month post-treatment visit by community health workers. Six- and 18-month follow-up visits will be used to assess effectiveness of these treatments against CIN2/3 and hrHPV. Nested studies will evaluate whether 1) specific HPV genotypes, CD4 and HIV viral load, and/or lesion size, location, and severity (i.e. imperfect adherence to WHO guidelines), are risk factors for treatment failures by each method and 2) deep-learning algorithms applied to digital images can predict ablative treatment failures and thereby used in the future to triage screen-positive women to LEEP instead of ablation and thereby potentially be avoided those treatment failures. Secondary analyses will assess the effectiveness of 12 different S&T strategies based on different combinations of 6 screening methods (hrHPV with no triage, hrHPV with triage using HPV genotype groups, hrHPV with VIA triage, hrHPV with AVE triage, VIA alone, or AVE alone) and two ablative methods.

NIH Research Projects · FY 2025 · 2020-03

SUMMARY Tumor-associated antigens, stress proteins, and danger-associated molecular patterns are endogenous immune adjuvants that can both initiate and continually stimulate an immune response against a tumor. In retaliation, tumors can hijack intrinsic immune regulatory programs, thereby facilitating continued growth despite an activated antitumor immune response. Clinically apparent tumors have co-evolved with the patient’s immune system and form a complex Tumor-Immune EcoSystem (TIES). The success of radiotherapy (RT) may be the result of radiation shifting the relative proportions of tumor and immune cells such that surviving cancer cells are subject to elimination by the immune system. However, current RT fractionation has not specifically focused on enhancing immune responses, nor has immune cell infiltration into the tumor as biomarker been considered to predict treatment response. We hypothesize that patients with a TIES such that radiation debulks the tumor and induces a robust immune response may be cured. A TIES with weak antitumor-immunity or strong immune suppression may not be sufficiently perturbed by current RT dose fractionation to fully harness radiation-immune synergy and provide tumor control. The goal of the project is to combine experimental studies and clinical data to calibrate and rigorously validate the in silico framework that simulates the influence of different TIES compositions on the response to different radiation doses and dose fractionations. We will focus on oropharyngeal cancer, one of the few cancer types increasing in incidence. In vivo tumors with and without tumor specific T cells provide radiation dose and fractionation-dependent changes in immune infiltration to derive in silico model parameters. For clinical analysis we will use a retrospective cohort of 51 oropharyngeal cancer (OPC) tissue samples as training cohort. We will prospectively collect radiosensitivity and immune infiltration data from 105 OPC patients that undergo radiation therapy with different total doses, dependent on their intrinsic radiosensitivity index (RSI). These data serve as a test cohort to validate model outcome predictions against clinical assessment of complete response at 3 months. Our overall aims are to determine radiation dose and fractionation that optimize radiation-induced immunity, and to identify how to use RT to shift a patient-specific TIES toward immune-modulated tumor elimination. These aims will motivate profound changes to how we conceive of and clinically prescribe RT. Radiation could be understood as immunotherapy. For patients with unfavorable TIES, RT fractionation protocols should focus on the radical perturbation of the TIES toward immune-modulated tumor control. For favorable TIES, dose could be de-escalated with focus on immune activation. Integrating our interdisciplinary expertise allows us to predict RT response and guide decision-making for individual patients, which holds the promise of leading to better outcomes. Successful project completion motivates an in silico model framework-aided clinical trial.

NIH Research Projects · FY 2025 · 2020-02

ABSTRACT Lung cancer is the global leader in cancer related deaths, and responsible for an estimated 1.4 million deaths worldwide and ~160,000 deaths in the United States annually. Treatment outcomes have improved in recent years with our recent understanding that patients can be divided into subsets based on the presence of specific genetic mutations that occur in their tumors. These oncogenic mutations can serve as predictive biomarkers that these tumors can be targeted with certain specific therapeutics. This approach has improved therapeutic options for patient with certain oncogenic mutations, but not the majority of patients. Ultimately, even the best responses to targeted therapeutics result in dramatic, but transient responses. A small population of cells remain refractory and survive, comprising what is known as minimal residual disease (MRD). MRD provides the molecular basis and roots that drive drug resistance - one of the most urgent clinical struggles in the war against cancer. In this proposal I set out to understand the role of WT EGFR or other ERBB family members in modulating oncogenic programs, the sensitivity to targeted therapies, and MRD in mouse and organoid models of lung cancer. The work described in this project will allow me to use elegant genetic systems to separate out the distinct role and contributions for WT EGFR from other ERBB family members in the context of some of the most common molecular subtypes of lung cancer. I will also be able to define the consequences of EGFR loss on MRD using state-of-the-art single cell RNA-sequencing technologies. Ultimately, the long-term goal of these analyses is to identify and understand the molecular mechanisms that drive MRD and the deployment of rational, targeted polytherapy strategies to eradicate MRD in malignant lung cancers.

NIH Research Projects · FY 2026 · 2020-01

Summary/Abstract Rapid advancements in identifying readers, writers, and erasers of epigenetic modifications, particularly in DNA and histone marks, have sparked increased interest in understanding their influence on protein-DNA interactions. This interest is driven not only by the essential role of these interactions in gene expression control but also by the emerging potential of DNA-binding transcription factors (TFs) as druggable targets. In mammals, DNA 5-methylcytosine (5mC) serves as a major epigenetic signal that regulates chromatin structure and, consequently, gene expression. Our research has revealed that many DNA-binding TFs are responsive to the CpG methylation status of their binding sites, including unmodified, 5mC, and successively oxidized forms (5-hydroxymethylC, 5-formylC, and 5-carboxyC). Despite these insights, significant challenges persist in unraveling how specific chromatin regions are targeted for methylation, oxidation, and demethylation, understanding the impact of CpG methylation on genome stability, and elucidating the coordinated effects of DNA and histone modifications on TF binding at DNA-regulatory elements to regulate the expression of specific genes.

NIH Research Projects · FY 2024 · 2019-09

Project Summary/Abstract: Childhood brain cancer is the most common solid tumor in children affecting approximately 2,500 children a year with an estimated 22,000 children living in the United States with a malignant brain tumor, which establishes this as an orphan disease. Current therapies for malignant childhood brain tumors including surgery, chemotherapy and radiation are very damaging to the developing brain of a child and can result in significant long-term disabilities such as cognitive difficulties, neuroendocrine dysfunction, and neurosensory deficits in survivors. Approximately 30-40% of children with malignant brain cancer do not survive, and high-grade tumors that recur after current therapies are uniformly fatal. Therefore, novel therapies which target tumor cells while sparing normal cells and stimulate an anti-tumor immune response are desperately needed. Oncolytic engineered herpes simplex virus (oHSV) therapy offers an inventive, targeted, less-toxic approach for children with incurable brain tumors and may afford an improved margin of safety as an adjuvant therapy for curable tumors allowing for lower doses and less toxicity from traditional therapies. HSV has been successfully engineered to introduce mutations in the virus (e.g. γ134.5 neurovirulence gene) that prevent infection in normal brain cells while maintaining the virus’ ability to kill cancer cells and stimulate an anti-tumor immune response. UAB conducted 3 Phase I trials of oHSV G207, which has both copies of γ134.5 deleted and an insertional deletion of the ribonucleotide reductase gene for added safety, given alone and with a single small dose of radiation to enhance virus replication and an anti-tumor immune response, in adults with recurrent high- grade glioma. These trials conclusively demonstrated safety of G207 inoculated intratumorally or in surrounding brain tissue, and ≈half of patients had radiographic evidence of tumor response, including two long-term survivors (>5.5 years). An active pediatric trial of G207 in supratentorial brain tumors has demonstrated safety of G207 alone with evidence of responses to G207 in 7 of 8 patients including a patient >21months post-G207 with an ongoing response without any additional therapies. These trial data coupled with our preclinical data demonstrating that aggressive pediatric brain tumors are highly sensitive to G207 and the lack of available therapies for patients strongly support an oHSV trial for children with progressive malignant cerebellar tumors. We propose to conduct a Phase I clinical trial of G207 alone and combined with a single low dose of radiation in children with recurrent cerebellar brain tumors. We hypothesize that G207 will be safe and tolerable with evidence of efficacy in children with refractory cerebellar malignancies. Our primary goal is to determine safety. Our secondary aims are to obtain preliminary information on the effectiveness of and immune response to G207 and on tumor genotypic and phenotypic features which may predict a response to oHSV. Importantly, this trial will support the clinical development of G207 for use in this devastating orphan disease.

NIH Research Projects · FY 2025 · 2019-09

Project Summary/Abstract Survival rates (app. 30 %) of acute myeloid leukemia (AML) have not been improved over 4 decades, except in some specialized instances. The long term aim of this study is to increase the cure rates of AML through clinical implementation of targeting a new cellular survival mechanism, i.e. mitochondrial (mt) unfolded protein response (mtUPR). We are proposing to conduct a clinical Phase 1/2 trial of ONC201, a first-in-class imipridone and to confirm and further investigate the underlying novel mechanism of action (MOA). We discovered in extensive preclinical studies that ONC201 induces apoptosis in AML but not in normal cells. Importantly, ONC201 has great efficacy in p53-mutated AML, the most chemotherapy-resistant subset, as well as in p53 wild-type AML. Our preclinical studies further demonstrate that ONC201 eliminates functionally- defined leukemia stem cells in patient-derived xenografts. Early trials initiated at MD Anderson show excellent tolerability of ONC201, micromolar plasma concentrations, and early clinical responses. We previously reported that ONC201 induces apoptosis mediated by the transcription factor ATF4, a hallmark of integrated stress response (ISR). However, ONC201 did not induce all characteristic molecular changes associated with classical ISRs (e.g., ER stress), suggesting an atypical MOA to induce ATF4. As break through progress reported in this re-submission, we have discovered that ONC201 directly binds and activates the mitochondrial protease, ClpP, resulting in selective mitochondrial proteolysis. The resultant reduction of mt protein pools induces so-called mt protein folding stress (mtPFS) and the protective transcriptional response against mtPFS termed mt unfolded protein response (mtUPR). Importantly, ATF4 is known to be induced through mtUPR, connecting our previous findings on ATF4 in a way different from classical ISRs. We here hypothesize that AML progenitor and stem cells are more susceptible to mtPFS than normal cells, and that ONC201 is targeting a novel point of vulnerability in AML pathobiology. The proposed clinical trial in leukemia provides a unique opportunity to thoroughly investigate this hypothesis. We will conduct a Phase 1/2 study of ONC201 in AML (Aim 1), and evaluate the underlying MOA (Aim 2). The Phase 1 trial will determine the safety and preliminary efficacy of ONC201 and Phase 2 the overall response rate. Changes in ATF4, mtUPR effector proteins, mt function and biogenesis in AML cells will be investigated using standard immunoblot and PCR methods as well as novel tools including CyTOF (single cell proteomics). We will also determine if ClpP, ATF4 and mtUPR effector proteins are potential biomarkers of clinical response to ONC201. Changes in clonal architecture will be monitored by flow cytometry and single-cell DNA sequencing. Genome-wide RNAseq will also be performed to further elucidate MOA and potential resistance. We expect these studies, which are at the cutting edge of our evolving knowledge of mitochondrial pathophysiology, to be developed into a highly effective and novel concept for the treatment of AML.

NIH Research Projects · FY 2025 · 2019-08

Cancer is second cause of death in the United States. Cancer prevention strategies represent the most promising means by which to reduce cancer-related deaths and cancer incidence. Feasibility of vaccines and cancer prevention drugs has been demonstrated in clinical trials targeting the prevention of cancer (recently renamed as ‘Cancer Interception'). Unfortunately, side effects associated with the use of these agents has limited their use. Therefore, there is an urgent need for more effective and less toxic cancer prevention interventions that healthy individuals would deem as both beneficial and tolerable. Our overarching goal is to continue developing the next wave of cancer interception agents by engaging our expert team of researchers to: 1. identify and develop novel effective and tolerable cancer interception strategies; 2. test the most promising of those strategies in early-phase cancer prevention clinical trials; and 3. translate these therapies to the clinic for individuals at high-risk of cancer. To this end, the MD Anderson “iCAN PREVENT” Consortium has renewed its commitment to cancer interception by bringing additional world leaders in cancer prevention, novel concepts for future clinical trials, updating our cores with state-of-the-art technologies (spatial transcriptomics, single-cell genomics), incorporating novel approaches to recruit and retain participants and incorporating a council of patient advocates combined with our pathology, systems biology, and statistics experts, to collaborate in the development of novel early-phase cancer interception clinical trials. With over 30 Phase I and II prevention trials conducted through our previous MD Anderson clinical trial consortia, our team brings knowledge and experience in the development and conduction of clinical trials while we incorporate novel ideas from junior investigators and new trial sites. To continue supporting these clinical trials, we focus on two aims: 1. testing the safety and efficacy of cancer prevention drugs, vaccines, and immune modulating interventions in individuals at high-risk for cancer development in >5 early-phase prevention trials; and 2. implementing the most novel methods to enhance recruitment and retention of participants to our trials. Included in this application are two sample trials: 1. a Phase II study testing low-dose enzalutamide for prostate cancer prevention in men with low-risk prostate cancer who are under active surveillance; and 2. a Phase II study comparing the efficacy of aerobic exercise, naproxen or the combination of both to modulate the immune system for cancer prevention in Lynch syndrome carriers. In addition, we present several potential concepts to be developed by our consortium. The results of our previous preventive studies have demonstrated that we are leaders developing new cancer interception strategies, which would provide the foundation to advance these interventions to Phase III with the ultimate goal of FDA-approval.

NIH Research Projects · FY 2025 · 2019-06

PROJECT SUMMARY Breakthroughs in cancer immunotherapy have excited patients and clinicians and have brought optimism back into the oncology community. However, these therapies are often effective for only a percentage of patients, and some patients may even be at risk for serious and sometimes fatal toxicities related to the therapy. Unlike the toxicities induced by standard therapies, immune-related adverse events (irAEs) are just becoming appreci- ated, and side effect profiles for new immunotherapies are often poorly understood. Further contributing to this issue is the increasing use of therapies that combine immune checkpoint inhibitors approved by the US Food and Drug Administration (eg, nivolumab, pembrolizumab) with other checkpoint inhibitors or targeted thera- pies. The unique toxicities of such combination therapies remain largely unknown and need to be tracked, so that their immune-related safety profiles can be characterized and adequately managed. Researchers at The Uni- versity of Texas MD Anderson Cancer Center propose to use patient-reported outcomes (PROs) to capture symptomatic irAEs of combination therapies that include checkpoint inhibitors, taking advantage of the large number of early-phase trials of these therapies already in place in the institution's Department of Investigational Therapeutics, coupled with the expertise in longitudinal symptom assessment in the Department of Symptom Research. The Specific Aims of the study are: (1) to identify, track, and evaluate emerging symptomatic toxic- ities and symptom burden during early-phase clinical trials of treatments that include immune checkpoint in- hibitors in combination with other checkpoint inhibitors or targeted therapies; and (2) to investigate relation- ships between longitudinal patient-reported symptoms and clinical outcomes (eg, development of moderate-to- severe irAEs, time to treatment discontinuation, time to deterioration) in early-phase trials of combination treat- ments that include checkpoint inhibitors, and to investigate whether moderate to severe irAEs are predicted by increases in relevant symptoms prior to the event. The study's clinical impact will be early detection of irAEs associated with combination therapies that include checkpoint inhibitors, to facilitate proactive intervention. Worsening symptoms may presage the emer- gence of their clinical manifestations and allow for appropriate supportive care or for other treatment decisions to be made. PROs are an essential component of cancer drug development, without which clinicians and regu- lators have an incomplete picture of how patients are affected by a new agent. PROs will provide invaluable pa- tient perspectives on the symptomatic effects of combination treatments that include immune checkpoint in- hibitors to multiple stakeholders in early drug development (eg, patients, sponsors, regulators, and payers). This project addresses Recommendation F in the Cancer Moon Shot Blue Ribbon Panel 2016 report, which calls for accelerated research to monitor and manage patient-reported symptoms, not only for improving quality of life, but also for ensuring patient adherence to treatments that will improve therapeutic response. 1

NIH Research Projects · FY 2023 · 2019-04

Modified Project Summary/Abstract Section The implementation of clinic-based Papanicolaou (Pap) test screening for cervical cancer has dramatically reduced the incidence of this disease in the US and other countries with widespread screening programs. However, many women remain at high risk for cervical cancer due to their inability or unwillingness to periodically attend for clinic-based screening. At present, evidence-based, client-directed strategies such as patient reminders and recalls, patient education, and patient navigation are the basis for many behavioral interventions to increase screening participation. However, these strategies alone are often unable to resolve many of the barriers faced by screening non-attendees. Using mailed self-sampling kits to test for high-risk human papillomavirus (HPV), the virus that causes cervical cancer, may overcome multiple barriers to clinic-based screening. However, this mailed self-sampling has not been evaluated in safety net health systems in the US that provide care for a large portion of lower-income and uninsured individuals. We hypothesize that in the context of a safety net health system, pairing mailed self-sample HPV testing with patient navigation, an outreach intervention with strong evidence for promoting use of preventive services, will have a synergistic effect for increasing screening participation among underscreened women. We propose to conduct a randomized controlled trial to compare the effectiveness of three outreach interventions to increase primary screening participation and clinical follow-up among underscreened women ages 30-65 years in a safety net health system. The trial setting is Harris Health System, the third largest publicly-funded safety net health system in the nation, which serves a predominantly racially/ethnically minority and lower-income population. The three study arms are: 1) telephone recall (control); 2) telephone recall with mailed self-sample HPV testing kits (intervention); and 3) telephone recall with mailed self-sample HPV testing kits and patient navigation (intervention plus). The primary outcome is primary screening participation. Secondary outcomes are predictors of screening and attendance for clinical follow-up among screen-positive women. Our study will also identify attitudes and experiences toward self-sampling among women who receive a mailed self-sampling kit and toward clinical follow-up among women who test positive for high-risk HPV. Finally, our study will evaluate the cost-effectiveness of mailed self-sample HPV testing, alone and in combination with patient navigation, to increase screening participation and reduce cervical cancer risk in safety net health systems. Collectively, these data will define the impact of self-sample HPV testing in a real-world health system setting, a critical step toward the development of scalable, cost-effective programs to eliminate cervical cancer disparities.

NIH Research Projects · FY 2025 · 2019-03

PROJECT SUMMARY-ABSTRACT Pneumonias cause millions of deaths annually and cause chronic health complications in many survivors. Yet, despite constant exposure of an immense surface area to the external environment, the lungs’ intrinsic defenses clear most pathogens before infections are established. These mucosal defenses can be therapeutically stimulated using a novel inhaled therapy comprised of a non-intuitive, synergistic synthetic pattern recognition receptor agonist combination. This inducible resistance results in rapid intrapulmonary pathogen killing and prevents death in mice from otherwise lethal pneumonias caused by bacterial, viral or fungal pathogens. Lung epithelial cells are principal mediators of this response, and reliance on airway and alveolar cells is fortuitous for patients with leukocyte-dependent immunocompromising conditions. The current proposal supports a program investigating the mechanisms by which this phenomenon protects against acute pneumonia and chronic lung disease, allowing greater understanding of native mucosal defenses, identifying populations most likely to benefit, and promoting development of more efficacious interventions against pneumonia. This program is designed to produce the greatest scientific advance and most robust training environment, so rather than targeting pre-specified milestones, investigations align within four self-sustaining enterprises that serially pursue testable hypotheses then iteratively build upon the generated data. Enterprise 1 dissects the mechanisms of synergistic signaling that drive pneumonia protection to reveal how optimized coincident detection can maximize the protective signal through novel sensors and amplifiers. Enterprise 2 pursues the mechanisms of inducible reactive oxygen species production to explain how sensing and signaling events promote coordinated generation of multisource antimicrobial volatile species. Enterprise 3 addresses the effector mechanisms that achieve broad pathogen killing to better define the extent of protection and investigate unexplored interactions of antimicrobial peptides and reactive oxygen species. Enterprise 4 explores the mechanisms that promote durably induced immunomodulatory effects to determine how inducible resistance exerts effects against asthma and immunopathology over extended time scales. These efforts will identify critical signaling events and effector mechanisms of inducible resistance, reveal unanticipated sensor interactions, facilitate discovery of more efficacious inducers of resistance, and expedite the translation of this technology into the clinic to protect patients during periods of peak vulnerability.

NIH Research Projects · FY 2026 · 2019-03

PROJECT SUMMARY Clinical trials are an integral part of MD Anderson Cancer Center’s (MDACC) mission. In FY2023, we cared for approximately 179,000 patients and enrolled more than 9,600 patients on nearly 1,500 interventional studies. MDACC has made significant contributions to the NCI cooperative groups and National Clinical Trial Network (NCTN), including robust trial enrollment, restructuring the scientific and administrative leadership, and mentoring early career faculty to participate in these important national trials. For FY 2019-2024, at MDACC, 1429 patients were enrolled in NCTN Network group clinical trials, including 1081 patients in therapeutic treatment trials resulting in an average of > 200 patients per year. Centralized coordination of NCTN activities at our institution has facilitated the development and conduct of multidisciplinary, innovative trials. This participation has led to opportunities for service through various NCTN leadership roles. Our institution has also sponsored talented clinical and translational investigators to apply for NCTN membership, provided mentorship of early career faculty, and encouraged applications for NCTN peer-reviewed grant funding. These activities have contributed to the success of the NCTN LAPS UG1 grant as well as working towards the fulfillment of our mission of eliminating cancer in Texas, nationally, and globally through advances in cancer treatment, research and education. Our goals will continue with the NCTN LAPS UG1 renewal grant.

NIH Research Projects · FY 2024 · 2019-01

PROJECT SUMMARY Glioblastoma is a lethal primary brain tumor with limited treatment options. The current standard therapy with combined chemoradiation therapy (chemoRT) with temozolomide (TMZ), an alkylating agent offers a median survival of only 16-18 months. There is an urgent need for novel therapies especially those that can overcome resistance to chemoRT. Cancer cells develop complex resistance mechanisms that enable them to survive the effects of conventional therapies. One such evolutionally conserved mechanism is the heat shock response (HSR) which can deploy several diverse defense processes in the setting of adverse environmental conditions. The HSR is mediated by heat shock proteins (HSP), a class of molecular chaperones that shuttle and configure client oncoproteins into proper functional states. In preliminary studies, we show that onalespib, a novel long acting inhibitor of heat shock protein 90 (Hsp90), a critical mediator of the HSR in cancer cells, blocked tumor growth, invasion and angiogenesis in gliomas suggesting the potential for a strong independent antitumor effect. Relevant to this proposal, onalespib sensitizes glioma cells to TMZ and RT in patient-derived (PDX) cell lines and in a zebrafish and mouse intracranial glioma animal models. Based on these data, in this grant submission, we propose a phase I clinical trial through the NCI-funded Adult Brain Tumor Consortium to identify the maximum tolerated dose of the combination of onalespib with chemoRT in adults with newly diagnosed GBM. We also propose to conduct key correlative tissue and plasma studies through the following specific aims: Aim 1 will identify the MTD of onalespib in combination of chemoRT and adjuvant temozolomide and will determine whether onalespib can cross the blood brain barrier and achieve sufficient concentrations in enhancing and non-enhancing glioma tissue compared with plasma levels. Aim 2 will determine the pharmacodynamic effects of onalespib by assessing whether onalespib can inhibit Hsp90, its target, in human GBM tissue obtained in this trial and whether this inhibition can affect its chaperone oncoprotein clients particularly those relevant to DNA repair and cell survival against the effects of RT and TMZ. In Aim 3, we will conduct co-clinical trials using PDX intracranial glioma models and organotypic human glioma slices to determine the mechanisms of sensitivity and resistance to onalespib effects to provide insights that can help modify the subsequent phase II trial. This is the first human trial of an Hsp90 inhibitor in brain tumors and the first to combine an Hsp90 inhibitor with chemo- and radiation therapy against GBM. Successful completion of this trial will enable us to proceed to a Phase II efficacy trial (approved by NRG oncology) and will provide comprehensive PK and PD data that can help the development of onalespib and Hsp90 inhibitors in other malignancies.

NIH Research Projects · FY 2025 · 2018-09

Project Summary: Intracellular Ca2+ signaling via changes in cytosolic Ca2+ concentration controls a wide range of cellular and physiologic processes. Ca2+ mobilization from intracellular stores mediated by second messengers plays a critical role in regulation of cytosolic Ca2+ levels. Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+-mobilizing second messenger identified to date; it uniquely mobilizes Ca2+ from acidic endolysosomal organelles. NAADP has been shown to be effective in evoking Ca2+ release in a multitude of different mammalian cells and defects in NAADP signaling are now being implicated in many diseases. Despite the importance of NAADP-evoked Ca2+ signaling, the molecular basis of NAADP-evoked Ca2+ release remains largely unclear. With immobilized NAADP–based affinity purification and quantitative proteomic analyses of NAADP and TPC interacting proteins, we identified Lsm12 to be a shared interacting partner of NAADP, TPC1, and TPC2. Lsm12 directly binds to NAADP via its Lsm domain, colocalizes with TPC2, and mediates the apparent association of NAADP to isolated TPC2 or TPC2-containing membranes. Lsm12 is essential and immediately participates in NAADP-evoked TPC activation and Ca2+ mobilization. Our findings thus reveal a putative RNA-binding protein functioning as an NAADP receptor and a TPC regulatory protein and provide a new molecular basis for understanding the mechanisms of NAADP signaling. Our further studies showed that Lsm12 has multifaceted function by affecting TPC channel gating properties and functioning in non-TPC dependent NAADP signaling. We hypothesize that: 1) Lsm12 as an NAADP receptor achieves its high selectivity and affinity to NAADP than NADP via its Lsm domain; 2) Lsm12 mediates TPC channel activation by NAADP via protein-protein interactions and/or dephosphorylation; and 3) Lsm12 can regulate multiple ion channels and mediate NAADP-evoked intracellular Ca2+ elevation via shared mechanisms. To test our hypotheses, we will pursue the following 3 specific aims. Aim 1. Determine the molecular mechanism of the Lsm domain in NAADP binding. Aim 2. Determine the molecular mechanisms of Lsm12-mediated TPC activation by NAADP. Aim 3. Determine the multifaceted function of Lsm12 in NAADP-evoked Ca2+ signaling. Findings from the proposed research will elucidate the molecular mechanisms and function of NAADP/Lsm12- mediated Ca2+ signaling and facilitate the development of new drugs for this important Ca2+ signaling process.

NIH Research Projects · FY 2025 · 2018-09

PROJECT SUMMARY/ABSTRACT Cancer is linked to every human DNA repair (DR) pathway. Genomic instability, which results from DR defects, is a cancer hallmark. Due to cancer cell susceptibilities from oncogenic stress and frequent DR defects, DNA damaging approaches are widely used successful cancer therapies. Yet, cancers may escape these therapies. Furthermore, they can cause toxicities, aging, and secondary cancers making knowledge to combat therapeutic resistance and to design advanced therapies important. In fact, DNA damage effects depend upon poorly understood dynamic DR complexes that are also a target for precision oncology. This R35 renewal application for Mesoscale and Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC) will focus on structures, mechanisms, and cancer cell biology impacts from exemplary systems addressing three critical knowledge gaps: 1) RNA alkylation response impacts on cancer cells, 2) DDR adaptors and complexes determining repair pathway choice at replication forks and DNA double-strand breaks (DSBs), and 3) mitochondrial sensing and response to PARylation and resulting changes in NADH levels. We will harness AlphaFold structure predictions for experimental structures including functional dynamicity and combine them with data analyses from whole genome studies (WGS) to determine how cancer genomes respond to damage, develop genome instability, and elaborate synthetic lethality for inhibitors to DDR. Alkylation therapies are widely used, but their damage to RNA, which is both more exposed to this damage and is roughly 10-fold higher than DNA, has unknown cancer cell impacts. Knowledge of DR pathway choice at DSBs and stalled forks remains incomplete. Although energy production and mitochondrial complex 1 is a cancer drug target how mitochondria respond to DNA damage and parylation, which lowers NADH levels, is enigmatic. Based upon his current R35 progress, Prof. Tainer is poised to efficiently test and define mechanisms underlying the outcomes to RNA alkylation responses, repair at DSBs and replication forks, and the mitochondrial response to high NADH use in DDR. With R35 support, we developed time-resolved X-ray scattering and its integration with atomic detail for conformations and assemblies that help link structures to phenotypes and biological outcomes. To elucidate how dynamic multi-functional DDR complexes orchestrate cellular responses to RNA damage, DNA damage at replication forks and breaks, and NADH levels, we will map their dynamic conformations and kinetics with systematic analyses. Rather than correlating data sets, we will integrate quantitative measurements to collapse complex data into unifying insights and actionable knowledge. Leveraging cutting-edge clinical information at MD Anderson will enable testing the relevance and impact of MANTIS-DRC predictions on patient databases. Collective results will produce objective mechanistic measurements from molecules to cells to design dissection-of-function mutations and inhibitor tools and to predict DR outcomes and their links to innate immune responses for cancer biology and medicine.

NIH Research Projects · FY 2025 · 2018-08

Abstract The overall goal of this renewal application is to validate biomarker signatures associated with aberrantly expressing pathways in pancreatic cancer for early stage PDAC detection among asymptomatic patients with high risk clinical, genetic and/or familial susceptibility characteristics. PDAC early detection signatures, developed with circulating transcriptomics, proteomics and metabolomics (omics) biomarkers identified in the first funding cycle, will be characterized for their association with heterogeneous disease subtypes and integrated with imaging-based disease subtype features derived with machine learning methods from CT/MRI scans reflecting functional changes in malignant lesions of the pancreas. Integration of Omics data with CT imaging features will be done by developing Multimodal Integrative Analytical Models (MIAM) predictive of early stage pancreatic cancer. Together, the pathway-based biomarker panels integrated with CT imaging data will define a novel clinically significant strategy for early detection and risk stratification. During the first funding cycle, a number of omics based circulating biomarkers were developed and validated in multiple sample cohorts from patients with early stage resectable disease. These together with additional candidate biomarkers in the pipeline will be further validated and investigated for their association with disease subtypes in Phases II, III and IV studies according to PRoBE-design in the renewal application. For phase IV studies, performance of the biomarkers in detecting disease and predicting clinical outcomes among asymptomatic patients and at-risk individuals will be ascertained with retrospective and prospective longitudinal pre-diagnostic sample cohorts, including one representing the underserved population. The innovative statistical approach of MIAM will be shared with other members of the consortia for rigorous validation and in the long term, we hope to translate the findings into developing open source software for use in clinical diagnostic laboratories in the future. Specific Aims of the PCDC grant are: Aim 1: Validation of pathway-associated biomarker signatures and novel CT imaging features for molecular subtype-related early stage PDAC and development of MIAM to integrate approaches for detection of early stage PDAC in Phase II cohorts. Aim 2: Validation of circulating Omics biomarkers and integration with precision imaging features in Phase III retrospective longitudinal pre-diagnostic cohorts for early detection and risk assessment. Aim 3: Prospective Screening and Validation of biomarker panels in Phase IV High Risk Cohorts- Aim 4: Participate in collaborative projects with other PCDC-RUs by sharing data/ideas and contribute in building biorepository and assay development using our unique technical and a

NIH Research Projects · FY 2025 · 2018-08

Research in the Hart Lab has focused on the central concepts of modular cell biology, as put forward by Hartwell et al, 1999: how normal cells rely on an interconnected web of biological processes for survival and proliferation, and how mutation rewires this web of dependencies into disease states. We have developed experimental and computational tools for CRISPR- mediated perturbation studies that provide an understanding of the hierarchical organization of the mammalian cell and reveal context-specific genetic vulnerabilities. Our work can be reasonably divided into research on first-order effects of gene perturbation, accurately measuring gene essentiality and differential essentiality, and second- order effects including digenic interaction, functional buffering, and network approaches. We developed the TKOv3 CRISPR/Cas9 genome-scale library for knockout screens in human and mouse cells (Hart et al, 2017), as well as the BAGEL (Kim & Hart, 2021) and DrugZ (Colic et al, 2019) software packages for analysis of fitness and chemogenetic interaction screens. Our integrative analysis of hundreds of cell-line screens from the Cancer Dependency Map initiative yielded one of the first coessentiality maps describing functional linkages between human genes (Kim et al, 2019); the first systematic survey of proliferation suppressor genes, discovering a novel putative tumor suppressor role for saturated fatty acid synthesis in myeloid leukemia (Lenoir et al, 2021); and one of the first integrated computational and experimental studies confirming that functional buffering by, e.g., paralogs is systematically missed by monogenic CRISPR/Cas9 knockout screens (Dede et al, 2020). These latter two works used the Cas12a CRISPR endonuclease and its endogenous multiplexing capability to build efficient assays for genetic interaction between targeted gene pairs. Our future work will deepen our understanding of how both first-order and second-order effects shape modular biology, and improve our ability to decipher the natural complexity of the cell by extending this work into higher-order effects from targeted polygenic perturbations. First- generation network approaches integrate functional linkage across all contexts; future computational work will decipher lineage-specific interactions to define more precise cellular networks for functional genomics and tissue-specific disease modeling. On the experimental side, we will continue to push the state of the art in genetic perturbation technology, developing a highly multiplexed and multimodal perturbation platform that can go beyond digenic interactions and provide deeper insight into the complexity of the mammalian cell.

NIH Research Projects · FY 2024 · 2018-07

ABSTRACT It is well known that cancer metabolism is highly dynamic and context- and oncogene-dependent. However, the underlying mechanism, particularly that of interorganelle communication in oncogene-dependent metabolic reprogramming, is largely unknown. Our preliminary studies establish that oncogenic MYC regulates Endoplasmic Reticulum (ER)-localized transmembrane sensor IRE1a and its substrate XBP1 via multiple mechanisms. Importantly, our pilot studies suggest the increased susceptibility of MYC-overexpressing triple negative breast cancer (TNBC) to IRE1a/XBP1 inhibition, possibly mediated via altered interorganelle communication and metabolic reprogramming to fatty acid oxidation (FAO). These findings provide a framework to seek biological insight into this altered communication between the ER, mitochondria, and nucleus in MYC-overexpressing TNBC cells, and to further explore the effects of pharmacological inhibition of IRE1a as an anti-tumor approach for MYC-driven TNBC by disrupting the interorganelle communication. We hypothesize that oncogenic MYC hijacks the ER stress sensor IRE1a, and its substrate XBP1, to promote mitochondrial FAO and sustain TNBC tumorigenesis and resistance to chemotherapy. This proposal will elucidate the function and mechanism of the ER in regulating MYC-driven oncogenic stress and mitochondrial metabolic reprogramming in TNBC. In Aim 1, we will investigate the biological significance of IRE1a/XBP1 mediated ER-nucleus communication in MYC-driven TNBC. Aim 2 will determine the role of mitochondrial FAO activation by the IRE1α/XBP1 pathway in MYC-driven TNBC. Lastly, Aim 3 will investigate the in vivo efficacy and mechanisms of combination therapy with IRE1a inhibitor and docetaxel in treating MYC-driven TNBC. The updated Aims for the 2-year extension period are based on the data generated from the original aims and represent a logical extension of the original aims to study the IRE1-mediated metabolic reprogramming and organelle dysfunction in regulating immunogenic cell death of MYC-driven TNBC. The resulting data from this proposal will be significant as they will promote the development of novel, mechanism-based therapeutic approaches to disrupt these altered metabolic pathways and improve the treatment of MYC-driven TNBC.

NIH Research Projects · FY 2025 · 2018-04

There is a critical need to train the next generation of translational cancer researchers in light of a new era of genomic medicine and big data. We must ensure that scientists are trained in the areas of highest need for translation of data and experiments into clinical practice. This application proposes renewal of the Translational Genomics and Precision Medicine Approaches in Cancer (TGP) training program developed at MD Anderson Cancer Center, where we have a single mission to eliminate cancer, in order to expand and enhance the training of outstanding predoctoral and postdoctoral fellows using an innovative curriculum and multidisciplinary approach centered on core competencies in state-of-the-art areas of translational research. Objectives: 1) to provide a comprehensive program with both depth and breadth in areas important to the future of translational cancer research including translational genomics and precision medicine approaches, early detection and prognosis of cancer, as well as diagnostic applications; 2) to recruit top predoctoral and postdoctoral fellows interested in a career in translational cancer research in this area; 3) to provide fellows with an innovative environment, and with the infrastructure, faculty and administrative support to allow them to make significant contributions to the field and further the mission of the MD Anderson Cancer Center. Rationale: TGP Training Program: The TGP program will provide the necessary education and training as well as infrastructure and oversight to develop innovative, big data genome scientists. A highly competitive selection process will identify outstanding candidates. Qualified candidates, in addition to a mentored research experience supervised by our outstanding training grant faculty, will gain individualized, interdisciplinary training in core competency areas critical to the future of translational science in a post-genome world. Design of T32 Program: The T32 will offer 3 postdoctoral and 3 predoctoral fellowships designed around core competencies which include: 1) translational cancer research, to gain exposure to mechanistic studies in translational research and their importance to the human organism; 2) precision medicine to gain experience in state-of-the-art approaches to diagnose and treat cancer patients; 3) translational genetics and genomics to gain competency in understanding and implementation of cancer precision medicine; 4) bioinformatics, to learn how to read and interpret large datasets; and 5) exposure to clinical grand rounds, tumor boards, and industrial collaborations. Key activities include state-of-the-art curriculum, tumor boards, exposure to NCI clinical trials network and MD Anderson strategic alliances between academia and industry, and focused mentoring. All trainees will be required to have a strong interest in cancer research and for post doctorates, experience in cancer research. The training duration will be 2 years for postdoctoral and 3 years for predoctoral fellows with training faculty at UT MD Anderson Cancer Center and the UT Graduate School of Biomedical Sciences.

NIH Research Projects · FY 2025 · 2018-04

Tissue damage responses are essential for multicellular organisms that occasionally encounter a hostile environment. These multi-tissue responses include epithelial barrier repair (wound healing), inflammation, and sensory responses like nociceptive sensitization. Together, these coordinated responses restore tissue functionality and/or protect the tissue from further damage while it heals. Our overarching hypothesis is that the biology of tissue repair arose early in the evolution of multicellular organisms. Consequently, many of the cellular strategies, signaling pathways, and behaviors that animals use to sense and to repair damage are ancient and evolutionarily conserved. Discovery of the basic cell biology and genetic underpinnings of these damage-induced responses is essential. Our long term goal is to identify the full suite of cells and genes that initiate and execute each tissue damage response and understand how these cells and genes function and work together to orchestrate successful repair of damaged tissues. My laboratory has pioneered the use of Drosophila larvae to study postembryonic tissue damage responses including wound closure, inflammation, and injury-induced nociceptive (pain) sensitization. During our first four years of MIRA funding we discovered important principles of wound edge adhesion dynamics, found a signaling pathway (related to vertebrate Vascular Endothelial Growth Factor [VEGF] signaling) required for spreading of inflammatory blood cells at wound sites, and explored injury-induced sensitization to cold, chemical, and mechanical stimuli. Our work over the next five years will focus on three key questions that emerge naturally from these prior studies: 1. How are adherens junction proteins (like β-Catenin) removed from the wound edge and how does this removal impact other wound-edge responses like actin polymerization? This question emerges from our observation that β-Catenin is rapidly removed from wound-edge membranes. With new tools we developed in the prior grant period we are in an excellent position to image this process in real-time at highly symmetric wounds and to discover which signaling pathways coordinate removal. 2. One key question with respect to inflammation is how inflammatory blood cells initially adhere to the wound. In our second project we will explore this key question and investigate the relationship between immune cell adhesion/spreading and immune cell function at the wound site. Our final project will seek to identify key functional downstream genes that mediate acute injury-induced nociceptive sensitization. This is a major gap in our understanding of this process and a key question in the study of nociceptive sensitization. My lab’s substantial history of creative high-impact research on diverse tissue damage responses suggests strongly that we will continue to make original strides and discoveries, especially if our ongoing grant-writing burden is lessened through the MIRA mechanism. Our system complements others in the field and the likelihood of continued novel basic insight into how organisms cope with tissue damage at the cellular and molecular/genetic levels is high.