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AACR-Bayer Innovation and Discovery Grants

The AACR-Bayer Innovation and Discovery Grants represent a joint effort to promote the key tenets of the Bayer Grants4Targets™ Initiative, providing new treatment options for cancers with high unmet medical need, encouraging innovation and translation of ideas from basic research into novel drugs, and fostering collaborations between academic groups and the pharmaceutical industry. Successful applications must focus on the following oncology research areas: inhibition of cell proliferation, survival signaling, transcription and chromatin modulation, cell cycle regulation, tumor metabolism, hypoxia, immunotherapy, antibody-drug conjugates.

2020 Grantees

James L. Chen, MD

James L. Chen, MD

Assistant Professor
The Ohio State University Comprehensive Cancer Center
Columbus, Ohio
Deciphering mechanisms of sorafenib sensitivity in desmoid tumors

Research
Desmoid tumors are rare tumors that are frequently recurrent and locally invasive. Desmoid patients often experience chronic pain, organ dysfunction, decrease in quality of life, and even death. Unfortunately, desmoid treatment remains a case of trial-and-error with no established biomarkers to predict treatment response. The oral drug, sorafenib, has emerged as a powerful front-line strategy. Although sorafenib reduces the risk of disease progression, less than a third of patients have an objective response. Thus, predictive biomarkers are critically needed to better identify sorafenib responders. We have collected numerous desmoid tumors as part of our sarcoma biobanking program. We plan to use the Biobank and desmoid patient-derived cell lines and examine their response before and after treatment with sorafenib. This will allow us to understand what genes are involved in sensitivity. If successful, we hope to test out these genetic biomarkers in a clinical trial.

Biography
Dr. Chen is a dually-appointed faculty member in the Departments of Internal Medicine and Biomedical Informatics. He is a recognized expert in the treatment of sarcoma and a translational bioinformatician. Along with serving as medical director for clinical and research informatics at the James Comprehensive Cancer Center, at the Ohio State University, Dr. Chen is active clinically and serves as principal investigator for several investigator-initiated sarcoma trials. His laboratory focuses on developing novel biomarkers and workflows for repurposing drugs in cancer using bioinformatics techniques. Dr. Chen chairs several national cancer workgroups in ASCO, the ALLIANCE Clinical Trials Group, and the Oncology Research Information Exchange Network (ORIEN).

Acknowledgment of Support
I am very grateful for this funding opportunity as it will provide critical data for better understanding how to tailor treatment for our patients with desmoid tumors.

Nicholas A. Graham, PhD

Nicholas A. Graham, PhD

Assistant Professor
University of Southern California
Los Angeles, California
Proteomic approaches to improve therapeutic targeting of PRMTs in glioma

Research
Gliomas, particularly high-grade glioblastomas, are aggressive brain cancers that have remained largely refractory to targeted therapeutic approaches. An emerging therapeutic approach is ‘collateral lethality’, whereby passenger deletion of a gene creates a druggable, tumor-specific vulnerability. One such collateral lethal interaction involves inhibition of the protein arginine methyltransferase 5 (PRMT5) in tumors with deletion of the 5-methylthioadenosine phosphorylase (MTAP) gene. However, there remain important mechanistic questions that need to be answered before PRMT5 inhibitors can be successfully clinically translated. Using a novel proteomic approach to globally measure how PRMT5 inhibitors regulate the protein arginine methylome, the Graham Lab will seek to identify the mechanistic basis of collateral lethality between PRMT5 inhibitors and MTAP deletion in patient-derived gliomasphere cultures. This project will thus advance brain tumor therapeutic research by enabling translational efforts to test PRMT5 inhibitors in glioblastoma, a deadly brain cancer in desperate need of new therapeutic options.

Biography
Dr. Graham is an assistant professor of chemical engineering at the University of Southern California. He received a BS in chemical engineering and French from Washington University in St. Louis, followed by an MS and PhD in chemical engineering from Caltech with Dr. Anand Asthagiri. He then completed an NIH-supported postdoctoral fellowship in molecular and medical pharmacology at the University of California, Los Angeles, with Dr. Thomas Graeber before joining the University of Southern California. His laboratory uses systems biology approaches including mass spectrometry-based proteomics and metabolomics to study cancer, aging, and diabetes.

Acknowledgment of Support
I am extremely grateful for the support provided by the 2020 AACR-Bayer Innovation and Discovery Grant. Support from this grant will allow my lab to use proteomic approaches to test new therapeutic approaches for patients suffering from the deadly brain cancer glioblastoma.

Willy Hugo, PhD

Willy Hugo, PhD

Assistant Professor
UCLA David Geffen School of Medicine
Los Angeles, California
Targeting the residual disease in MAPK inhibitor treated melanoma

Research
About 50% of all melanomas harbor a mutated form of the gene BRAF. The introduction of mutant-specific BRAF inhibitors and their combinations with MEK inhibitors (hereafter referred to together as MAPK pathway inhibitors or MAPKi) has significantly improved mutant BRAF melanoma patients’ survival, yet this therapy rarely results in complete eradication of a patient’s tumor. One of the most reported resistance-conferring adaptations under MAPKi is the emergence of melanoma cells with diminished melanocytic phenotype, as evidenced by low expression of the MITF protein and high expression of the AXL protein. As such, most of the recent studies to overcome MAPKi resistance have been focusing on finding ways to suppress the MITF-low, AXL-high melanoma cells. Intriguingly, based on our melanoma patient-derived data, MAPKi-treated patient tumors do not show the MITF-low, AXL-high phenotypic switch as frequently as observed in the wet lab experimental setup. This observation has an important clinical implication: we may have been trying to overcome a resistance mechanism that is not prevalent in real patient tumors. We posit that the discrepancy is driven by the presence of immune and stromal cells in patient tumors. Thus, this proposal plans to test for novel therapeutic vulnerabilities of MAPKi-treated melanoma cells in the presence of relevant immune/stromal cells and their factors in order to accurately model the emergence of MAPKi resistance in melanoma patients.

Biography
Dr. Hugo earned his PhD in computational biology from the National University of Singapore in 2011 and published multiple high impact papers on the mechanisms of resistance to targeted- and immunotherapy in melanoma during his postdoctoral training under the mentorship of Dr. Roger Lo at the University of California, Los Angeles (UCLA). Currently, Dr. Hugo is an assistant professor at the Department of Medicine, UCLA. His laboratory is studying the role of the interaction between tumor cells and the immune/stromal cells in the tumor microenvironment and how such interaction influences the development of resistance toward targeted- and immunotherapies in cancer.

Acknowledgment of Support
The 2020 AACR-Bayer Innovation and Discovery Grant will allow me to study and test novel therapeutic targets in MAPK inhibitor resistant melanoma. Importantly, this project will dissect the development of MAPK inhibitor resistance phenotype in the presence of immune and other normal cells, which can better mimic the true environment in which tumors grow. With this grant support, I am confident that our team can discover novel therapeutic opportunities that can be exploited to improve the efficacy and durability of MAPK inhibitor therapy in melanoma patients.

Edward L. Schwartz, PhD

Edward L. Schwartz, PhD

Professor of Medicine and Molecular Pharmacology
Albert Einstein College of Medicine
New York, New York
A novel druggable target for tumors with a mutant RB1 tumor suppressor gene

Research
The RB1 tumor suppressor gene is mutated and inactivated in highly aggressive tumors, including virtually all small cell lung cancers, where its loss, along with TP53, is required and sufficient for tumorigenesis. While it is known that RB1 mutant cells fail to arrest at the G1/S checkpoint, this information has not led to effective strategies, as it is challenging to develop targeted drugs for tumors that are driven by the loss of gene function. Skp2 is a substrate recruiting subunit of an SCF E3 ubiquitin ligase and is a repression target of pRb. In mice in which lung and prostate tumorigenesis was driven by the loss of RB1, the concurrent knockout of Skp2 completely blocked tumor growth and metastasis, thereby validating Skp2 as a potential drug target in RB1-deficient tumors. The objective of this proposal is to design, synthesize and test small molecule inhibitors of Skp2, a downstream actionable target in RB1-deficient cancers.

Biography
Dr. Schwartz received a doctorate in pharmacology and toxicology from Michigan State University and did postdoctoral training in the Department of Pharmacology at Yale University. Dr. Schwartz uses his expertise in cancer biology and experimental therapeutics toward the identification of new targets for drug design and development for the treatment of cancer. His current research focuses on agents that induce tumor cell death by novel mechanisms, including the regulation of proteins that control the cell cycle and the modulation of cell signaling.

Acknowledgment of Support
I am honored to be an awardee of the AACR-Bayer Innovation and Discovery Grant. This funding provides a pathway to translate our mechanistic findings to the discovery of novel therapeutics to treat tumors that are deficient in the RB1 tumor suppressor gene, aggressive cancers for which there are no effective drugs. I extend my gratitude to the AACR and Bayer for their support.

Shobha Vasudevan, PhD

Shobha Vasudevan, PhD

Associate Professor
Massachusetts General Hospital Cancer Center
Boston, Massachusetts
Targeting post-transcriptional regulation underlying chemoresistance

Research
Our studies showed that stress-induced, post-transcriptional mechanisms drive distinct gene expression that allow therapy survival in resistant cancers. This includes cytokines and immune receptors that block apoptosis and antitumor immunity. We re-purposed small molecules that are used to suppress cytokines in fibrosis and a non-toxic kinase inhibitor to block stress signals and prevent resistance in leukemia. These pathways are observed in refractory triple negative breast cancer, suggesting an avenue to improve current therapies. The goal is to target the posttranscriptional expression of survival regulators that are induced by therapy stress signals using our inhibitors to curb refractory triple negative breast cancer. We will combine our inhibitors with clinical therapies, in patient samples and syngeneic models and patient derived xenografts in immune-competent mice, to test if the inhibitors block resistance and restore anti-tumor immunity. This study will test new resistance inhibitors in vivo, and improve therapy against resistant breast cancer.

Biography
Dr. Vasudevan is an associate professor of medicine at Massachusetts General Hospital Cancer Center and Harvard Medical School. Her research is focused on the role of RNA mechanisms underlying resistant cancers as a basis for designing new therapies. Her laboratory discovered that quiescent cells use specialized post-transcriptional mechanisms to promote gene expression important for cancer persistence. Dr. Vasudevan completed her doctorate with Dr. Stuart Peltz at Rutgers University-UMDNJ and her postdoctoral fellowship with Dr. Joan Steitz at Yale University. She has received several awards including from the RNA Society, Leukemia and Lymphoma Society, Cancer Research Institute, V Foundation, and Leukemia Research Foundation.

Acknowledgment of Support
I am honored to receive the AACR-Bayer Innovation and Discovery Award, which will enable us to progress our findings toward clinical applications. This can complement current therapies to improve patient outcomes and promote collaboration with the AACR community.

2019 Grantees

 Eleonora Dondossola, PhD

Eleonora Dondossola, PhD

Instructor
University of Texas MD Anderson Cancer Center
Houston, Texas
Targeting kinases in castration-resistant prostate cancer bone metastasis

Research
Prostate Cancer (PCa) is a leading cause of cancer related deaths in U.S. males, with bone metastasis as a major complication of tumor progression. Despite the development of novel life-prolonging therapies, the initial response is often followed by disease relapse. Kinase enzymes are key players in basic biological processes that support the function of both normal and altered cells, including PCa. Dr. Dondossola will test the hypothesis that PCa progression in bone critically depends on kinase-driven mechanisms and that their targeting could significantly reduce the evolution of the disease. By applying unbiased machine learning approaches (in collaboration with Dr. T. Gujral, Fred Hutchinson, Seattle), a series of naïve candidate kinase inhibitors (KI) have been predicted to significantly reduce PCa cell growth. The preclinical relevance of candidate KIs will be investigated using 3D bone mimetic environments and in vivo experiments.

Biography
Dr. Dondossola received her BSc in medical and pharmaceutical biotechnology followed by a MSc in molecular and cellular medical biotechnology and a PhD in cell and molecular biology (Vita-Salute San Raffaele University, Italy). As a scientist committed to the fight against cancer, in 2011 she moved for her postdoctoral training to UT MD Anderson Cancer Center, where she was promoted to instructor in 2016. Her research focuses on the role of microenvironment in tumor progression and treatment. Recently, she further expanded her studies to tissue-engineered technologies for inflammation and cancer research, with an emphasis on prostate cancer bone metastasis and its therapeutic targeting.

Acknowledgment of Support
The 2019 AACR-Bayer Innovation and Discovery Grant will allow me to understand the importance of altered kinases and underlying networks as targets for therapy in metastatic PCa to bone. This project aims to provide efficacy predictions that can provide a basis for innovative therapeutic strategies, with relevance for clinical practice.

Malay Haldar, MD, PhD

Malay Haldar, MD, PhD

Assistant Professor
University of Pennsylvania
Philadelphia, Pennsylvania
Regulation of sarcoma lung metastases by a novel IL13-endothelin axis

Research
Soft tissue sarcomas (STS) are a relatively rare and heterogeneous group of cancer arising from connective tissue. Surgical resection, chemotherapy, and radiation can be effective in localized STS. However, metastatic STS are resistant to treatment and have very poor prognosis. Lung is the most common site of metastases in STS, but the molecular mechanism controlling this process is poorly understood. Dr. Haldar’s group has been studying tumor-infiltrating leukocytes in STS and found that interleukin-13 produced by intratumoral leukocytes may play an important role in lung metastases through modulation of endothelin signaling. The goal of this proposal is to identify the molecular underpinnings of this pathway and target it for the control of pulmonary metastases.

Biography
Dr. Haldar is an assistant professor in the pathology department at the University of Pennsylvania. He obtained his medical degree from B.J. Medical College at the University of Pune in India and completed a PhD in human genetics at the University of Utah. He then went on to do a residency in clinical pathology and post-doctoral research in immunology at Washington University in St. Louis before starting his independent research group at UPenn in 2015. Dr. Haldar’s research focusses on molecular determinants of tumor-immune interaction and his clinical expertise is in molecular diagnostics.

Acknowledgement of Support
I am very honored to receive the AACR-Bayer Innovation and Discovery Grant. This generous support will help translate our basic science discoveries into new treatment strategies in soft tissue sarcomas, a group of rare but lethal cancers where treatment options are very limited.

Zaneta Nikolovska-Coleska, MS, PhD

Zaneta Nikolovska-Coleska, MS, PhD

Associate Professor
University of Michigan
Ann Abor, Michigan
Dual Mcl-1/Bfl-1 inhibitors: A new weapon against metastatic melanoma

Research
Significant progress has been made in the treatment of metastatic melanoma, but drug resistance represents a major clinical challenge. Anti-apoptotic Bcl-2 family members Mcl-1 and Bfl-1 have emerged as critical survival factors for melanoma cells and key molecules implicated in acquired resistance. The goal of this project is to study the simultaneous inhibition of Mcl-1 and Bfl-1 as an attractive therapeutic strategy to overcome apoptotic resistance. Employing structure-based drug design, Dr. Nikolovska-Coleska and her team developed a new class of potent small molecule dual Mcl-1/Bfl-1 inhibitors, inducing Bax/Bak- and caspase-dependent apoptosis. BH3 profiling studies demonstrated that the Mcl-1 and Bfl-1 dependency was enhanced in vemurafenib melanoma resistant cell lines, which were more sensitive to the dual inhibitors in comparison with the parental cells. In this project, dual inhibitors will be further optimized for potency and in vivo efficacy and evaluated pre-clinically and mechanistically as a potential novel effective melanoma treatment.

Biography
Dr. Nikolovska-Coleska is an associate professor of pathology and a member of the Rogel Cancer Center, Michigan Medicine. She received her BSc in pharmacy and MSc and PhD in pharmaceutical chemistry from Ss. Cyril and Methodius University, Skopje, Republic of Macedonia. She completed postdoctoral training in drug discovery with Professor Wang at the University of Michigan and in 2008 joined the faculty of the pathology department. She serves as Director of Pathology Graduate Program and Associate Director of Program in Biomedical Sciences. Her research aims to discover and develop targeted therapies focusing on protein-protein interactions involved in controlling apoptosis and epigenetics.

Acknowledgement of Support
I am honored to accept the AACR-Bayer Innovation and Discovery Award. This support will enable our project to move forward with the development and characterization of dual Mcl-1/Bfl-1 inhibitors and to translate our findings to more effective and safer treatments for patients with metastatic melanoma.

Jill P. Smith, MD

Jill P. Smith, MD

Professor
Georgetown University
Washington, DC
The CCK-B receptor: A novel target for therapy of hepatocellular carcinoma

Research
The fastest growing cause of cancer-related death is hepatocellular carcinoma (HCC), which is in part attributable to the obesity epidemic and nonalcoholic steatohepatitis (NASH). Therapy with immune checkpoint antibodies has shown promise in HCC, but responses remain only 25-40 percent. Dr. Smith has been studying cholecystokinin (CCK) and its receptor in gastrointestinal cancers. Her team discovered that CCK-receptors are low or absent on normal hepatocytes but become over-expressed in NASH and HCC. In preliminary data she showed that a CCK-receptor antagonist, proglumide, prevented HCC and reversed fibrosis in mice with NASH. In this proposal, Dr. Smith will study the effects of blocking the CCK-receptor with antagonists alone or in combination with immune checkpoint antibodies. She will study the role of the CCK-receptor in human liver cancer cells and in HCC tumors in mice. Proglumide is an old drug that was developed for peptic ulcer disease and is safe in humans.

Biography
Dr. Smith is a professor of medicine in gastroenterology and hepatology at Georgetown University. She is also professor emeritus at Pennsylvania State University. Dr. Smith was the former Director of Clinical & Translational Research at NIDDK, NIH. She is a clinical scientist and has dedicated her entire academic career to patient care, teaching students, and conducting research. Her passion has been bench-to-bedside research, and she has several patents. Her basic science research has focused on G-protein-coupled receptors, in particular cholecystokinin receptors and their role in GI cancers. She was elected the first female president of the American Pancreatic Association.

Acknowledgement of Support
Being a hepatologist, it was difficult having my own father die during a liver transplant for cirrhosis and one of my best friends die of hepatocellular carcinoma. I am grateful for the 2019-AACR-Bayer Grant, which will allow me to explore our novel therapy with the CCK-receptor antagonist proglumide.

Eric T. Wong, MD

Eric T. Wong, MD

Associate Professor
Beth Israel Deaconess Medical Center
Boston, Massachusetts
CSF metabolomic biomarkers to predict CNS response to cancer immunotherapy

Research
My translational research focusses on brain metastasis and how systemic tumors migrate into the brain. In melanoma brain metastases, we determined that there are specific profiles of chemokines and cytokines that enable the reconfiguration of the immune milieu in the brain, making it possible for brain metastases to occur. We have accumulated a large collection of cerebrospinal fluids that can be linked to the clinical status of patients. The goal is to use these fluids to investigate the basic biology of brain metastases from various types of systemic malignancies, then conduct translational clinical trials. We are uniquely positioned to identify relevant biomarkers in the cerebrospinal fluid, with the ultimate goal of facilitating the diagnosis and monitoring of brain metastases, as well as developing personalized treatments.

Biography
Dr. Wong is the director of the Brain Tumor Center and neuro-oncology unit at Beth Israel Deaconess Medical Center and associate professor of neurology at Harvard Medical School. He obtained an undergraduate degree in electrical engineering from the University of Pennsylvania, followed by graduate study at Rutgers Medical School, training in neurology residency at Washington University Medical Center in St. Louis, and subspecialized neuro-oncology fellowships at Memorial Sloan Kettering Cancer Center and the MD Anderson Cancer Center. He is a fellow of the American Neurological Association and serves on the neuro-oncology protocol committee at the Harvard/Dana-Farber Cancer Center in Boston. Dr. Wong investigates the utility of cerebrospinal fluid biomarkers that can predict treatment responses in brain tumor patients. He has served on the editorial boards of the Journal of Clinical Oncology and Cancer Medicine and as a past president of the Massachusetts Society of Clinical Oncologists.

Acknowledgement of Support
The 2019 AACR-Bayer innovation and Discovery grant will enable me to pursue translational research on biomarkers in the cerebrospinal fluid that may predict the efficacy of immune therapy for brain metastasis. The overarching goal is to develop personalized immune therapy for patients with metastatic cancer in the central nervous system.

2018 Grantees

Richard L. Bakst, MD

Richard L. Bakst, MD

Associate Professor
Icahn School of Medicine at Mount Sinai
New York, New York
Targeting monocyte recruitment and macrophage function for perineural invasion

Research
Cancer can spread or metastasize through a variety of mechanisms. Certain cancers specifically invade and disseminate along local nerves, termed perineural invasion (PNI). Despite the widespread acknowledgement of its significance, there are currently there are no targeted therapies for PNI. The current inability to interrupt this aggressive cancer phenotype represents a highly unmet clinical need. We previously demonstrated that the immune system plays a significant role in promoting nerve invasion by cancer. In response to cancer, the nerve secretes a molecule that recruits circulating monocytes, which arrive at the nerve and promote nerve invasion through the production of a specific enzyme that disrupts protective layers surrounding nerves. We aim to target this conserved innate immune response rather than specific cancer properties to impair nerve invasion. This approach has the potential to generate novel treatment strategies to impact a broad range of solid tumors that display PNI.

Biography
Dr. Bakst is an associate professor of radiation oncology and otolaryngology at the Icahn School of Medicine at Mount Sinai in New York City. Dr. Bakst earned his MD from New York University School of Medicine in 2007, where he graduated with honors. He completed his residency in radiation oncology at Memorial Sloan-Kettering Cancer Center in 2012, where he served as chief resident. His research focuses on elucidating the mechanisms by which cancer invades and disseminates along nerves.

Acknowledgement of Support
I am honored to have been selected as a recipient of the AACR-Bayer Innovation and Discovery Grant. Through this support, I aim to translate our mechanistic findings into novel treatment strategies to inhibit this aggressive cancer phenotype.

Christine Fillmore Brainson, PhD

Christine Fillmore Brainson, PhD

Assistant Professor
University of Kentucky
Lexington, Kentucky
Synergy of copanlisib with epigenetic inhibitor in PIK3CA-driven NSCLCs

Research
Precision medicine for lung cancer is poised to revolutionize treatment of this deadly disease. PIK3CA, the gene that encodes P110a, the catalytic subunit of the intracellular signaling kinase termed PI3K, is activated in 50 percent of squamous lung cancers by both mutation and genomic amplification. Many PI3K inhibitors have been developed, but these drugs have failed to be efficacious at targeting PIK3CA-driven lung cancers in clinical trials. Our preliminary data suggest that responses to PI3K inhibitors, such as the FDA-approved copanlisib, are greatly increased by addition of a drug targeting the epigenetic enzyme EZH2. The goals of this proposal are to establish a mouse model in which to test this promising drug combination and to determine the mechanism of EZH2 inhibitor and PI3K inhibitor synergy. If successful, this research could result in a new precision medicine opportunity that would be beneficial for a large number of lung cancer patients.

Biography
Born and raised in Massachusetts, Dr. Brainson has always wanted a career in cancer research. She joined the faculty of the University of Kentucky in the Toxicology and Cancer Biology Department in October of 2016. She trained at Dana-Farber Cancer Institute with Dr. Charles Roberts and at Tufts University with Dr. Charlotte Kuperwasser. She was a postdoctoral fellow at Boston Children’s Hospital, where she worked with Dr. Carla Kim and Dr. Kwok Wong. The Brainson Lab focuses on defining precision medicine opportunities for lung cancer by leveraging ideas and techniques from stem cell biology and epigenetics.

Acknowledgement of Support
I am thrilled to accept the AACR-Bayer Innovation and Discovery Award. It will allow my lab to develop a PI3K-driven mouse model of lung cancer in which to test a promising drug combination. We are hopeful that our research will positively impact the large number of patients with PI3K-driven tumors.

Michael Mitchell, PhD

Michael Mitchell, PhD

Assistant Professor
University of Pennsylvania
Philadelphia, Pennsylvania
High-throughput in vivo discovery of microRNA leukemia therapeutics

Research
Despite dramatic improvements in survival using current therapies, relapse is the most frequent cause of cancer-related death among children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This is due, in part, to disease progression, drug resistance, and a lack of targeted drug delivery systems. MicroRNAs play a critical role in the initiation, progression, and drug resistance of ALL, and microRNA-based therapies can potentially overcome ALL drug resistance by reducing the expression of oncogenes. However, microRNA therapies have been hampered by a lack of efficacious nucleic acid delivery systems. As a novel paradigm for ALL therapy, we propose a nanotechnology platform that delivers microRNA therapeutics, reduces systemic toxicity, and overcomes ALL resistance to clinical therapeutics. The proposed studies have the potential to improve public health and patient outcomes through new therapeutics that alleviate suffering, replace less efficacious options, and reduce the overall treatment cost of ALL and potentially other hematologic malignancies.

Biography
Dr. Mitchell is the Skirkanich assistant professor of innovation in the Department of Bioengineering at the University of Pennsylvania and a member of the Abramson Cancer Center at the Perelman School of Medicine at Penn. His lab designs novel biomaterials and drug delivery systems with applications in cancer therapy, immunoengineering, and gene editing. He received a BE from Stevens Institute of Technology in 2009 and a PhD from Cornell University in 2014, both in biomedical engineering. He was a postdoctoral fellow at the Koch Institute for Integrative Cancer Research at MIT from 2014 to 2017. He was named an AACR Scholar in Cancer Research in 2016 and is the recipient of an NIH Ruth L. Kirschstein National Research Service Award, the Burroughs Wellcome Fund Career Award at the Scientific Interface, and the NIH Director’s New Innovator Award.

Acknowledgement of Support
Our lab currently develops novel polymer and lipid nanoparticles to deliver gene therapeutics in vivo to multiple myeloma. Generous support from the AACR-Bayer grant will enable our lab to broaden the use of our gene delivery platform technology to develop next generation therapeutics for acute lymphoblastic leukemia.

Anurag Singh, PhD

Anurag Singh, PhD

Assistant Professor
Boston University
Boston, Massachusetts
Co-targeting PAK kinase and Bcl family proteins in NRAS dependent melanoma

Research
Despite advances in targeted and immune therapies for melanoma treatment, many patients face poor clinical prognoses. NRAS is mutated in 20 percent of melanomas and is an upstream activator of the RAF/MEK/ERK, PI3K/AKT, and RAC1/PAK kinase signaling pathways, which cooperate to drive melanomagenesis. Preliminary data indicates that NRAS-mutant melanoma cell lines can be classified into NRAS-dependent and NRAS-independent subtypes. This dichotomy was exploited to reveal an NRAS dependency transcriptional signature that is enriched with kinase genes, including MAP3K7/TAK1 and PAK3. A combinatorial compound screen showed that PAK kinase inhibition in combination with Bcl2/Bcl-XL inhibition causes synergistic cell death of NRAS-dependent melanoma cells. Aim 1 of this research proposal will be to validate the therapeutic efficacy of combined PAK kinase and Bcl-2/Bcl-XL inhibition in xenografted NRAS-dependent melanomas in immunodeficient mice. Aim 2 is to define PAK isoform-specific functions in NRAS-dependent melanoma cells by CRISPR-cas9 genetic ablation of PAK isoforms 1-6.

Biography
Dr. Singh received his PhD in pharmacology from the University of North Carolina at Chapel Hill. His postdoctoral research at the Massachusetts General Hospital, Harvard Medical School focused on deeper mechanistic understanding of oncogenic KRAS signaling. He performed seminal work on the derivation of lineage-specific transcriptional signatures of mutant KRAS dependency. Dr. Singh is currently an assistant professor in the Pharmacology and Experimental Therapeutics Department at Boston University School of Medicine. His current research is focused on understanding drug resistance mechanisms in KRAS and NRAS mutant cancers, including melanoma.

Acknowledgement of Support
I am honored to receive an AACR-Bayer Innovation and Discovery Grant. This funding gives me the capability to test and develop a new combinatorial therapeutic strategy for melanoma treatment. The grant will put me in a good position to receive federal funding for the project and enhance my career development.