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.

2021 Grantees

Research
High N-Myc levels are correlated with poor therapeutic outcomes in neuroblastomas. N-Myc is frequently stabilized in tumor cells by Aurora kinase A (Aurora-A). Dr. Harki and his laboratory have developed a chemical strategy to rapidly deplete N-Myc protein levels through the targeted protein degradation of Aurora-A. The novel Aurora-A degraders were found to inhibit the growth of MYCN-amplified neuroblastoma cells with good potency. In this study, he aims to generate second-generation Aurora-A/N-Myc-degrading compounds with improved potency, selectivity, and drug-like properties.

Biography
Dr. Harki received a BA in biology and in chemistry from West Virginia University, where he performed organic synthesis research. He then pursued a PhD in chemistry from Penn State University on the development of antiviral nucleosides, followed by postdoctoral studies at the California Institute of Technology investigating the regulation of transcription factor signaling in cancer with pyrrole-imidazole polyamides. He joined the Department of Medicinal Chemistry at the University of Minnesota in 2009 and is currently a Northrop Professor. Research in the Harki laboratory focuses on the development of novel chemical probes and therapeutics.

Acknowledgment of Support
The long-term goal of the project is to develop a new therapy for the treatment of childhood neuroblastomas. I am very grateful to receive an AACR-Bayer Innovation and Discovery Grant to support our drug discovery efforts.

Research
Despite advances in treatments, 20-50% of T-cell acute lymphoblastic leukemia (T-ALL) patients relapse and ultimately die, highlighting the need to discover novel therapies. Dr. Herranz’s preliminary results show potent antileukemic activity with a novel mitochondrial uncoupling drug. However, leukemic cells treated with this drug as single agent eventually became resistant and relapse. Thus, in this project he aims to dissect the mechanisms of resistance to mitochondrial uncoupling and to identify synergisms with currently used chemotherapeutic drugs in T-ALL patients.

Biography
Dr. Herranz obtained his PhD at the Spanish National Cancer Research Center working on the role of Sirt1 in metabolism, cancer, and aging. He pursued postdoctoral training at Columbia University, where he focused on the transcriptional and metabolic dependencies of T-cell leukemia. In 2017, he established his own independent research program at Rutgers Cancer Institute of New Jersey, where he has already made significant contributions uncovering novel enhancer regions in leukemia as well as novel therapeutic targets for the treatment of this disease.

Acknowledgment of Support
My long-term goal is to become a leader in leukemia translational studies. This AACR-Bayer Innovation and Discovery Grant is widely recognized as an extremely prestigious award, bestowed only to the most innovative projects. Thus, it will be instrumental to consolidate my career as well as to propel our studies using mitochondrial uncoupling drugs.

Research
Using the latest developments in gene editing, direct targeting of oncogenic mutations with CRISPR/Cas can be a highly innovative therapeutic approach. Like all genetic tools, the CRISPR/Cas machinery must be delivered directly to target cells’ nuclei to be safe and effective. However, current delivery platforms such as adenovirus, lentiviral vectors, and synthetic delivery methods induce off-target effects and lack tissue tropism toward the lung. Dr. Momen-Heravi’s lab has recently developed a novel customizable delivery platform based on engineered exosomes which are devoid of endogenous nucleic acids, called SafeExo-Cas. SafeExo-Cas express endogenous Cas protein and contain targeting moieties toward lung tissue. In this project, she and her group aim to optimize the use of this delivery platform to deliver CRISPR/Cas machinery to lung tissues to treat lung cancer.

Biography
Dr. Momen-Heravi received a DDS from Tehran University, Iran, an MPH from Harvard University, and a PhD in molecular biology/biotechnology from the University of Westminster, U.K. She pursued residency training in periodontics at Columbia University and performed postdoctoral research in molecular biology at Harvard Medical School and the University of Massachusetts Medical School. She is currently an assistant professor at the Herbert Irving Comprehensive Cancer Center and the College of Dental Medicine at Columbia University. Her lab works on novel genome editing modalities based on CRISPR/Cas and exosomes as precision medicine tools to treat cancer. Her group also combines computational biology and advanced biostatistical methods with wet lab techniques to identify signaling mechanisms and tumor vulnerabilities in head and neck cancer and lung cancer.

Acknowledgment of Support
I am honored to be an awardee of the AACR-Bayer Innovation and Discovery Grant. This funding provides a pathway to develop our novel exosome-based therapeutic platform into novel therapeutics to treat lung cancer. I extend my gratitude to the AACR and Bayer for supporting innovation in cancer research.

Research
Although mutant KRAS can be silenced in vitro by RNAi, attempts to target KRAS in vivo have been met with obstacles and, therefore, this oncogene has been labeled as “untargetable.” The cholecystokinin-B receptor (CCK-BR) is not found in normal pancreas but becomes overexpressed in precancerous PanIN lesions and in pancreatic cancer. Dr. Smith’s group has developed a biodegradable fluorescent polyplex nanoparticle that selectively targets the CCK-BR that can carry a siRNA payload to inhibit growth of human pancreatic cancer in mice. In this project, fluorescent CCK-BR targeted nanoparticles will be used to deliver mutant KRAS siRNA to high grade PanINs using the mutant Kras (LSL-KrasG12D/+;P48-Cre) mouse model in order to prevent PanIN progression. In addition, the KRAS siRNA loaded nanoparticles will be used to treat orthotopic established pancreatic cancer in immune competent mice.

Biography
Dr. Smith is a professor of medicine at the Lombardi Comprehensive Cancer Center at Georgetown University. Dr. Smith also practices at the Washington DC Veterans Affairs Medical Center. As a clinical scientist, Dr. Smith has dedicated her entire academic career to patient care, teaching, and conducting research. Her passion has been bench-to-bedside translational research. Her basic science research has focused on G-protein-coupled receptors, in particular cholecystokinin receptors and their role in gastrointestinal cancers.

Acknowledgment of Support
The outcome of our work could lead to a new approach for targeting KRAS in pancreatic cancer. This fluorescent target-specific nanoparticle, or theranostic agent, can be developed for both treatment (therapy) and early detection (diagnosis) of high grade PanIN-3 lesions in order to prevent pancreatic cancer. We would like to acknowledge support for this project from the 2021 AACR-Bayer Innovation and Discovery Grant.

Research
Increasing matrix stiffness in breast tumors is a prognostic marker of distant metastasis and poor survival. In addition to biochemical pathways, an equally promising therapeutic avenue to combat breast tumor metastasis is to target novel mechanotransduction pathways. Dr. Yang and her lab have uncovered a novel mechanotransduction pathway that promotes epithelial-mesenchymal transition (EMT) in response to mechanical cues in the tumor microenvironment, thereby impinging on tumor invasion and metastasis. They identified a mechanosensitive EPHA2/LYN protein complex that functions upstream of the EMT transcription factor TWIST1 to promote TWIST1 nuclear localization and consequently EMT and metastasis. In this project, they aim to test whether targeting the EPHA2/LYN mechanotransduction signaling pathway could inhibit breast cancer invasion and metastasis.

Biography
Dr. Yang obtained her PhD in molecular cancer biology at Duke University. In 2000, Dr. Yang became a Damon Runyon Cancer Research Foundation postdoctoral fellow at the Whitehead Institute for Biomedical Research. Dr. Yang joined the faculty of University of California, San Diego in 2006 and is currently a professor in the Department of Pharmacology, Pediatrics and Moores Cancer Center at the University of California, San Diego. Her work identified epithelial-mesenchymal transition as being critical for tumor invasion and metastasis. Her group continues to study epithelial-mesenchymal plasticity in tumor progression.

Acknowledgment of Support
I am so grateful and honored to receive the 2021 AACR-Bayer Innovation and Discovery Grant. This support will allow us to push our basic cancer research discovery from the bench side to be one step closer to clinical translation. Thank you for supporting innovative cancer research.

2020 Grantees

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.

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.

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.

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.

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

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.

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.

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.

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

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.

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.