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.

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. 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. Dr. Chen is using their Biobank to develop desmoid patient-derived cell lines, examine the response before and after treatment with sorafenib, and identify genes involved in sorafenib sensitivity.

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.

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. Using a novel proteomic approach to globally measure how PRMT5 inhibitors regulate the protein arginine methylome, the Graham Lab seeks to identify the mechanistic basis of collateral lethality between PRMT5 inhibitors and MTAP deletion in patient-derived glioma sphere cultures.

Biography
Dr. Graham received his PhD in chemical engineering from Caltech. He then completed an NIH-supported postdoctoral fellowship in molecular and medical pharmacology at the University of California, Los Angeles, before joining the University of Southern California. He is currently an assistant professor of chemical engineering. 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
One of the most reported MAPKi resistance-conferring adaptations involves the emergence of melanoma cells with diminished melanocytic phenotype, as evidenced by low expression of the melanocyte inducing transcription factor (MITF) and high expression of the AXL protein. Yet, previous melanoma patient-derived data from Dr. Hugo’s research group showed that MAPKi-treated patient tumors do not show the MITF-low, AXL-high phenotypic switch as frequently as observed in the wet lab experimental setup. They posit that this discrepancy is driven by the presence of immune and stromal cells in patient tumors. Thus, to accurately model the emergence of MAPKi resistance in melanoma patients, he is testing for novel therapeutic vulnerabilities of MAPKi-treated melanoma cells in the presence of relevant immune/stromal cells and their factors.

Biography
Dr. Hugo earned his PhD in computational biology from the National University of Singapore. He pursued postdoctoral training at the University of California, Los Angeles (UCLA), where he studied mechanisms of resistance to targeted- and immunotherapy in melanoma. Currently, he 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
Albert Einstein College of Medicine
New York, New York
A novel druggable target for tumors with a mutant RB1 tumor suppressor gene

Research
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. Dr. Schwartz is designing, synthesizing, and testing 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. He is a professor of medicine (oncology) and molecular pharmacology at Albert Einstein College of Medicine. 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
Previous work by Dr. Vasudevan has shown 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. Dr. Vasudevan’s research group has previously shown that post-transcriptional mechanisms play a role in therapy resistance. Clinical therapy can induce DNA damage and stress signals, resulting in the phosphorylation of an RNA binding protein and deregulation of a survival program that is normally suppressed. Dr. Vasudevan aims to therapeutically target the posttranscriptional expression of these therapy induced-survival regulators in triple negative breast cancer.

Biography
Dr. Vasudevan completed her doctorate at Rutgers University-UMDNJ and her postdoctoral fellowship at Yale University. She 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.

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
Dr. Dondossola hypothesizes that prostate cancer (PCa) progression in bone depends on kinase-driven mechanisms and that targeting these mechanisms could significantly reduce the evolution of the disease. By applying unbiased machine learning approaches, a series of naïve candidate kinase inhibitors (KI) have been predicted to significantly reduce PCa cell growth. She is investigating the preclinical relevance of these candidate KIs using 3D bone mimetic environments and in vivo experiments.

Biography
Dr. Dondossola received her PhD in cell and molecular biology at Vita-Salute San Raffaele University, Italy. She pursued postdoctoral training at MD Anderson Cancer Center, where she has been promoted to instructor. Her research focuses on the role of the 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. 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 has found that interleukin-13 produced by intratumoral leukocytes may play an important role in lung metastases through modulation of endothelin signaling. He aims to identify the molecular underpinnings of this pathway and target it for the control of pulmonary metastases.

Biography
Dr. Haldar obtained his medical degree from B.J. Medical College at the University of Pune in India and his PhD in human genetics at the University of Utah. He pursued residency in clinical pathology and post-doctoral research in immunology at Washington University in St. Louis. He is currently an assistant professor in the pathology department at the University of Pennsylvania. His research focuses 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
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. Dr. Nikolovska-Coleska is exploring the potential of the simultaneous inhibition of Mcl-1 and Bfl-1 as an attractive therapeutic strategy to overcome apoptotic resistance. Employing structure-based drug design, she and her team previously developed a new class of potent small molecule dual Mcl-1/Bfl-1 inhibitors. They aim to optimize these dual inhibitors for potency and in vivo efficacy and then evaluate them pre-clinically and mechanistically as potential novel effective melanoma treatment.

Biography
Dr. Nikolovska-Coleska received her PhD in pharmaceutical chemistry from Ss. Cyril and Methodius University, Skopje, Republic of Macedonia. She completed postdoctoral training in drug discovery at the University of Michigan and subsequently became an associate professor of pathology and a member of the Rogel Cancer Center, Michigan Medicine. 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 nonalcoholic steatohepatitis (NASH). Dr. Smith’s team discovered that cholecystokinin (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 project, Dr. Smith is studying the effects of blocking the CCK-receptor with antagonists alone or in combination with immune checkpoint antibodies. In addition, she is set to interrogate the role of the CCK-receptor in human liver cancer cells and in HCC tumors in mice.

Biography
Dr. Smith is a professor of medicine in gastroenterology and hepatology at Georgetown University. She is also professor emeritus at Pennsylvania State University. She was the former Director of Clinical & Translational Research at NIDDK, NIH. Her basic science research has focused on G-protein-coupled receptors, in particular cholecystokinin receptors and their role in GI cancers.

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
Dr. Wong and his research group previously determined that there are specific chemokine and cytokine profiles that enable the reconfiguration of the immune milieu in the brain, making it possible for brain metastases to occur. They have accumulated a large collection of cerebrospinal fluids that can be linked to the clinical status of patients. They are using these fluids to investigate the basic biology of brain metastases from various types of systemic malignancies.

Biography
Dr. Wong pursued graduate education 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 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 investigates the utility of cerebrospinal fluid biomarkers that can predict treatment responses in brain tumor patients.

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
Dr. Bakst and his research group 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. Dr. Bakst and his research group aim to target this conserved innate immune response to impair nerve invasion.

Biography
Dr. Bakst earned his MD from New York University School of Medicine, where he graduated with honors. He completed his residency in radiation oncology at Memorial Sloan-Kettering Cancer Center, where he served as chief resident. He is currently an associate professor of radiation oncology and otolaryngology at the Icahn School of Medicine at Mount Sinai, where he 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
Although many PI3K inhibitors have been developed, these drugs have failed to be efficacious at targeting PIK3CA-driven lung cancers in clinical trials. Preliminary data from Dr. Brainson’s research group 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. She is establishing a mouse model in which to test this promising drug combination and to determine the mechanism of EZH2 inhibitor and PI3K inhibitor synergy.

Biography
Dr. Brainson trained at Dana-Farber Cancer Institute and at Tufts University. She was a postdoctoral fellow at Boston Children’s Hospital. She joined the faculty of the University of Kentucky in the Toxicology and Cancer Biology Department, where her laboratory is 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
MicroRNA-based therapies can potentially overcome acute lymphoblastic leukemia (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, Dr. Mitchell is developing a nanotechnology platform that delivers microRNA therapeutics, reduces systemic toxicity, and overcomes ALL resistance to clinical therapeutics.

Biography
Dr. Mitchell received his PhD in biomedical engineering from Cornell University. He was a postdoctoral fellow at the Koch Institute for Integrative Cancer Research at MIT. He 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 laboratory designs novel biomaterials and drug delivery systems with applications in cancer therapy, immunoengineering, and gene editing.

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
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. Dr. Singh aims to validate the therapeutic efficacy of combined PAK kinase and Bcl-2/Bcl-XL inhibition in xenografted NRAS-dependent melanomas in immunodeficient mice. In addition, he aims 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 the 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.