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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.

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

Scientific Statement of 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

Scientific Statement of 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.

Daniel A. Harki, PhD

Daniel A. Harki, PhD

Associate Professor
University of Minnesota
Minneapolis, Minnesota
Chemical inhibition of APOBEC-catalyzed tumor evolution

Scientific Statement of Research
APOBEC enzymes are a component of the innate immune defense and function by catalyzing cytosine-to-uracil deamination in foreign, single-stranded DNA. However, tumor cells can exploit the mutagenic activity of APOBEC enzymes, and APOBEC3B in particular, to catalyze sub-lethal levels of genomic mutations that contribute to disease progression and drug resistance. Therefore, APOBEC3B is an attractive target for developing drugs to slow or prevent the development of drug resistance mutations in cancer. Our team will utilize an NMR-based screening approach to discover small molecule fragments that bind the active site of APOBEC3B. Top scoring fragments will then enter an optimization campaign that leverages medicinal chemistry, computational chemistry, structural biology, and biochemical assays. The anticipated outcome of this project is the discovery of novel APOBEC3B ligands that can be further developed into potent and selective APOBEC3B enzymatic inhibitors in future work.

Biography
Dr. Harki received a BA in biology and chemistry from West Virginia University (1999), where he performed research on anticancer natural product analogues (with Kay Brummond). Dr. Harki then pursued a PhD in chemistry from Penn State University (2005) on the development of antiviral nucleosides (with Blake Peterson), followed by postdoctoral studies at Caltech (2005-2009) investigating the regulation of transcription factor signaling in cancer with pyrrole-imidazole polyamides (with Peter Dervan). Dr. Harki joined the University of Minnesota in 2009. Research in the Harki laboratory focuses on the development of novel chemical probes for studies on DNA-interactive proteins.

Acknowledgement of Support
The long-term goal of our project is to harness APOBEC3B-catalyzed tumor evolution to prevent the development of drug resistance mutations that defeat cancer therapies. I am grateful to receive this AACR-Bayer Innovation and Discovery Grant, which will support our efforts to discover novel APOBEC3B-regulating molecules.

 Joshua J. Meeks, MD, PhD

Joshua J. Meeks, MD, PhD

Assistant Professor
Northwestern University
Chicago, Illinois
Targeting FGF in bladder cancer after neoadjuvant immunotherapy and surgery

Scientific Statement of Research
Therapeutic treatment of bladder cancer with checkpoint immunotherapy (CPI) has resulted in durable survival for responders, but features that define resistance remain unclear. The FGFR pathways, predominately driven by FGFR3, are altered in up to half of bladder cancers and are often associated with resistance to both chemotherapy and immunotherapy. In this project, Dr. Meeks will evaluate the overexpression of FGFR pathways in pre-CPI tumors from the PURE-01 cohort treated with Pembrolizumab to determine if this is a viable target found more in CPI-resistant tumors. If FGFR-responsive tumors could be identified prior to treatment, combination of ICB with FGFR targeting therapy may improve the overall response, resulting in a significant impact of survival for patients with bladder cancer.

Biography
Dr. Meeks is an assistant professor in the departments of urology and biochemistry and molecular genetics at Northwestern University and the Jesse Brown VAMC. He trained at Northwestern University and Memorial Sloan-Kettering and is a urologic oncologist treating genitourinary cancers. Dr. Meeks’s research is focused on basic and translational mechanisms of progression and resistance of epigenetic and immunotherapies in urothelial carcinoma.

Acknowledgement of Support
This 2019 AACR-Bayer Innovation and Discovery Grant provides the pathway to translate the hypothesis from an important clinical trial led by my collaborator, Andrea Necchi, to investigate mechanisms of new therapeutics. We hope to identify a susceptibility that can be targeted to improve survival of patients with bladder cancer.

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

Scientific Statement of 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.

Jason Sheltzer, PhD

Jason Sheltzer, PhD

CSHL Fellow
Cold Spring Harbor Laboratory
Cold Spring Harbor, New York
Targeting a novel CDK dependency in cancer

Scientific Statement of Research
While screening mischaracterized anti-cancer agents Dr. Sheltzer and his group discovered a small molecule drug that kills cancer cells by potently inhibiting the cyclin-dependent kinase CDK11B. This compound is the first specific inhibitor of the CDK11 family to be described. However, little is known about the function of this kinase or its role in cancer cells. Additionally, CDK11B harbors a 97 percent-identical homolog called CDK11A that may confound analyses by substituting for CDK11B function. Dr. Sheltzer will use CRISPR and this compound to investigate the consequences of ablating CDK11A and CDK11B in a variety of cancer types. This project will greatly increase knowledge of a novel cyclin-dependent kinase dependency in cancer and may allow identification of a genomic biomarker that can predict sensitivity to its inhibitor.

Biography
Dr. Sheltzer received an AB in molecular biology from Princeton University and a PhD in biology from the Massachusetts Institute of Technology. Following graduation, he established his own research group as an independent fellow at Cold Spring Harbor Laboratory. The Sheltzer Lab applies in vitro, in vivo, and in silico approaches to understand the genetic changes that underlie cancer development and progression, focusing on the consequences of chromosome-scale gene dosage imbalances.

Acknowledgement of Support
We are grateful for the support of the AACR. The AACR-Bayer Innovation and Discovery Grant will allow my lab to study CDK11, a protein that may be a promising target for future therapeutic development.

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

Scientific Statement of 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

Scientific Statement of 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.

Yong Zhang, PhD

Yong Zhang, PhD

Assistant Professor
University of Southern California
Los Angeles, California
Targeting renal cell carcinoma with novel immunotherapeutics

Scientific Statement of Research
Cell-derived exosome nanovesicles have emerged as an increasingly attractive class of therapeutics. Given their unique and pharmacologically important characteristics, Dr. Zhang proposes to develop novel exosome-based immunotherapeutics and evaluate their therapeutic activity and specificity using preclinical models. It is expected that these novel exosome-based therapeutics may allow the immune system to attack tumor cells with enhanced efficacy and safety, resulting in new therapeutic candidates for better treatment of renal cell carcinoma (RCC). This study, if successful, may lead to the development of an innovative class of immunotherapeutics for RCC.

Biography
Dr. Zhang is a tenure-track assistant professor of pharmacology and pharmaceutical sciences and chemistry of the University of Southern California. Dr. Zhang received his BS in biological sciences from Shandong University in 2003 and his MS in biophysics from the University of Guelph in 2006. He earned his PhD in biochemistry with Professor Vern L. Schramm at Albert Einstein College of Medicine in 2011. Dr. Zhang received postdoctoral training with Professor Peter G. Schultz at the Scripps Research Institute and California Institute for Biomedical Research from 2011 to 2014.

Acknowledgement of Support
The generous support from the AACR-Bayer Innovation and Discovery Grant will not only allow me to carry out the proposed important work but also recognize the significance of my original research and enhance the visibility of my research program.

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

Scientific Statement of 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

Scientific Statement of 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

Scientific Statement of 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

Scientific Statement of 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.