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.
- Andrew C. Dudley, PhD
- Angela N. Koehler, PhD
- Brunhilde H. Felding, PhD
- Christine M. Eischen, PhD
- David B. Lombard, MD, PhD
- Geou-Yarh Liou, PhD
- John R. Basile, DDS, DMSc
- Nathanael S. Gray, PhD
- Ryan A. Wilcox, MD, PhD
- Shobha Vasudevan, PhD
Andrew C. Dudley, PhD
University of Virginia
Targeting dysfunctional tumor blood vessels with vascular-tropic miR-30c mimics to prevent the growth of metastatic seeds
Even in microscopic tumors, tumor-associated blood vessels are dysfunctional and leaky which allows fibrinogen and other plasma proteins to accumulate in a perivascular niche. Extravascular fibrin creates scaffolds for invasive cancer cells and it forms a lattice for new blood vessels to sprout. Our lab has recently uncovered a vascular-directed and drug-accessible pathway that controls the rate of fibrin degradation and tumor progression. We show that enhancing endothelial cell expression of miR-30c using vascular-tropic nanoparticles diminishes expression of the serpine1 gene (serpine1 encodes for PAI-1 which is the major "break" on fibrinolysis). We also find that targeting this pathway is sufficient to promote rapid vascular-driven fibrinolysis which inhibits tumor growth in an orthotopic mammary tumor model. For this project, we seek to extend these studies to a model of experimental metastasis. Because extravascular fibrin may be a "spark" that supports the growth of disseminated cancer cells, we propose that promoting rapid fibrin degradation using vascular-tropic miR-30c conjugates will inhibit metastatic outgrowth.
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Angela N. Koehler, PhD
David H. Koch Institute for Integrative Cancer Research at MIT
Attenuation of oncogenic Myc-driven transcription via a Max-directed small molecule in lung adenocarcinoma
Overexpression of the MYC oncogene, which encodes a master regulator transcription factor, is associated with most types of human malignancies. Inactivation of Myc in murine model systems or using the dominant negative peptide Omomyc elicits oncogene addiction and tumor regression. Despite intense effort from multiple sectors, Myc-directed therapeutics are lacking. As such, our lab has explored alternative strategies to attenuate Myc-driven transcriptional programs, including perturbation of Myc's heterodimer partner Max with small molecules. The Myc/Max heterodimer activates transcription while the Max homodimer competes for the same genomic target sites, attenuating Myc-driven programs. An emerging hypothesis is that the tumor suppressor activity of Max relies on its ability to modulate Myc-driven programs via the homodimer. As such, our lab screened for direct small-molecule binders to Max using small-molecule microarrays (SMMs) in an effort to identify compounds that bind to Max and modulate Myc-driven transcription. We identified a unique small molecule, KI-MS2-008, that binds to Max, inhibits Myc-driven transcription with submicromolar potency, and stabilizes the Max homodimer while reducing Myc protein levels. KI-MS2-008 phenocopies MYC inactivation in a variety of cellular readouts and displays anti-tumor activities in vitro and in vivo using Myc-driven models of T-ALL and hepatocellular carcinoma. Inspired by previous work demonstrating eradication of K-ras-driven lung cancer in mice via Omomyc, we now seek to expand in vivo evaluation of KI-MS2-008 to lung adenocarcinoma. We will evaluate biodistribution, toxicity, and efficacy of KI-MS2-008 in a conditional mouse model of NSCLC with tumor initiating K-ras activation and loss of p53. We will establish MTD and execute standard PK/PD studies followed by evaluation of KI-MS2-008 efficacy. Through these efforts, we aim to clarify the role of Max as a direct therapeutic target for malignancies with aberrant Myc function.
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Brunhilde H. Felding, PhD
The Scripps Research Institute
La Jolla, California
Cancer specific mutant protein structures as immune therapy targets
We seek to identify cancer specific mutant protein structures on highly aggressive and hard-to-treat cancers, and to develop antibodies against these novel targets for diagnosis and therapy. Our focus is on genetic mutations in proteins expressed at the tumor cell surface that can be recognized by the immune system as unique to the cancer. In this study, we singled out a known disease driver in multiple neoplasms whose mutant forms are associated with the disease. We are targeting RET tyrosine kinase in medullary thyroid carcinoma (MTC). RET protein is known to be mutated in endocrine cancers, and in its mutant forms suspected to promote uncontrolled cell growth. Mutations in transmembrane receptor tyrosine kinases, such as RET, may impact protein structure including multimerization state, receptor trafficking from protein production to display on the cell surface, signaling pathways that may activate cell proliferation, migration and invasion, and the ability of tumor cells to metastasize. We identified a novel combination of RET mutations in a patient with an unusually aggressive MTC. One of the mutations impacts disulfide bonds, and our results suggest that a multimer forms that is constitutively active, and mostly likely assumes a cancer specific protein conformation. A second mutation may impact the tyrosine kinase functionality and further drive cell signaling events. Our study focuses on these mutations, as well as on known mutations affecting the Cys-rich region of RET in endocrine neoplasms. Our overall goals are to analyze the cancer specific mutant structures of RET, develop conformation-specific antibodies against cancer-associated mutant RET, and determine antibody specificity and targeting ability in unique, new preclinical models of MTC and in clinical endocrine neoplasms with defined RET mutant status. This part of the study is dedicated to purifying wild type and mutant RET protein variants, isolating conformation-specific antibodies against cancer-associated mutant RET from recombinant patient and human germline immunoglobulin libraries, and to work toward 3D structure analysis by x-ray crystallography and cryo electron microscopy at Å-resolution.
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Christine M. Eischen, PhD
Thomas Jefferson University
Using PROTACS to target the Mdm2 oncoprotein
Half of all human cancers have inactivated the p53 tumor suppressor prior to any treatment. Resistance to some treatments can occur through mutation of p53. Loss of functional p53 confers increased survival and growth advantages to cancer cells. p53 is regulated by the Mdm2 oncoprotein, which was believed to be unnecessary to the cancer cell once p53 was inactivated. However, we recently made the paradigm-shifting discovery that cancer cells that have lost p53 require Mdm2 for their survival. This knowledge opens new avenues for treating cancers that have inactivated p53 through targeting Mdm2. With the development of proteolysis-targeting chimeras (PROTACs), individual proteins can be specifically targeted for degradation. Together with a medicinal chemist, we have designed and generated the first Mdm2-directed PROTAC. Initial tests show that this PROTACs kills malignant cells that have inactivated p53. We propose to further evaluate this PROTAC on multiple types of cancer cells and increase optimization of it for in vivo testing in pre-clinical mouse models. We also propose to generate additional Mdm2-directed PROTACs. Results from our studies should ultimately lead to improved therapeutic intervention for the many malignancies that have inactivated p53.
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David B. Lombard, MD, PhD
University of Michigan
Ann Arbor, Michigan
A novel therapeutic target in uveal melanoma
Uveal melanoma is the most common tumor arising within the eye. Uveal melanoma differs in many important respects from its much more frequent cousin, cutaneous melanoma. It possesses a distinct set of genetic changes rarely found in the latter cancer. Unfortunately, roughly 50% of patients with uveal melanoma eventually develop metastases, typically to the liver or lungs. Disseminated uveal melanoma is resistant to standard melanoma treatments, such as kinase and immune checkpoint inhibitors. Consequently, current 5-year survival rates for patients with metastatic uveal melanoma remain dismal. This proposal focuses on the SIRT5 protein as a novel potential therapeutic target for uveal melanoma. SIRT5 is a sirtuin, a member of a protein family that promotes cellular and organismal homeostasis in mammals. SIRT5 is found mainly in mitochondria, and regulates hundreds of target proteins in diverse pathways by removing specific modifications on lysine residues. Although normal cell types and whole mice tolerate loss of SIRT5 with minimal effects, we have found that specific cancer types -- notably including uveal melanoma cells -- are exquisitely dependent on SIRT5, and rapidly undergo apoptosis following SIRT5 depletion. We have identified novel small molecule SIRT5 inhibitors that we are beginning to evaluate as new candidate cancer therapies. Using metabolite measurements and gene expression analyses, we will mechanistically elucidate the dependency of uveal melanoma on SIRT5, and test the efficacy of SIRT5 inhibitors against these cells. If successful, this work will eventually pave the way for new treatments for metastatic uveal melanoma, a cancer with no current effective therapy.
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Geou-Yarh Liou, PhD
Clark Atlanta University
Targeting inflammatory cytokine signaling during initiation and development of pancreatic cancer
Pancreatic cancer is the most disastrous type of cancer with an extremely low 5-year survival rate, which has remained unchanged over 4 decades and is projected to become 2nd leading death among all cancer-related fatalities. The greatest challenge of bringing down the death toll of pancreatic cancer patients is to detect and intervene this disease at its early stage. The Liou laboratory identified oncogenic Kras-upregulated inflammatory cytokines during PDAC initiation and progression. This proposal will reveal the mechanism of how the identified cytokines modulate the processes of initiation and development of PDAC using 3D organoid cultures and relevant animal models. Results from this project will provide insight into the potential use of targeting the cytokines in the clinic not only as a preventive measure for the high-risk populations for pancreatic cancer (e.g. hereditary pancreatitis), but also for intervening tumor progression in patients who have early stage pancreatic cancer. By preventing from getting pancreatic cancer or restraining cancer cells in the pancreas will significantly improve the death numbers of pancreatic cancer.
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John R. Basile, DDS, DMSc
University of Maryland School of Dentistry
Inhibition of semaphorin 4D in the treatment of bone homing malignancies
Bone density is controlled by factors produced by osteoclasts, which resorb bone, and osteoblasts and osteocytes, which deposit and maintain the mineralized matrix. The semaphorins and their receptors, the plexins, originally shown to activate inflammatory cells and provide chemotactic cues for axon guidance, are now known to play a role in this process. Emerging data have identified Semaphorin 4D (S4D) as a product of osteoclasts that acts through its receptor Plexin-B1 (PB1) on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Some cancers overexpress S4D, so we theorized that bone-homing malignancies could be exploiting this pathway to establish lytic skeletal lesions. The treatment of choice to suppress skeletal spread in cancer is anti-resorptive medication, which suppresses bone remodeling and increases the risk of medication-related osteonecrosis of the jaw (MRONJ). Patients suffering from prostate cancer, breast cancer, or primary skeletal malignancies are often managed with these medications for years, increasing the risk of MRONJ and suggesting the need for a less harmful therapeutic approach. The broad objective of our project is to demonstrate the importance of S4D and PB1 in cancer progression to bone. The hypothesis to be tested is that cancer cell S4D facilitates osteolysis through osteoblast hypoactivity and osteoclastogenesis, and that its inhibition could elicit the protective effects as anti-resorptive medications without the adverse sequelae of MRONJ.
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Nathanael S. Gray, PhD
Dana-Farber Cancer Institute
DCLK1 kinase inhibition as a targeted therapy for K-Ras mutant pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) ranks among the most deadly cancers. The most significant genetic alterations in PDAC are activating missense mutations in the small GTPase K-Ras, which occur in 90- 95% of cases. Years of research have established that mutant K-Ras plays an active role in the initiation and progression of pancreatic tumorigenesis, yet there is still a great unmet need for therapies that are effective in K-Ras mutant cancers. As mutant K-Ras is highly challenging to drug itself, an alternative approach is to target its effector pathways. Recent data from studies in the mouse pancreas have revealed that doublecortin and calcium/calmodulin-dependent kinase-like 1 (DCLK1) is important for pancreatic progenitor maintenance and tumor initiation. Moreover, DCLK1 is proposed to be a mutant K-Ras effector protein that supports tumorigenesis in the human pancreas. We have found using mass spectrometry (MS) that DCLK1 expression is up-regulated in preneoplastic K-Ras mutant pancreas, and that its expression increases during tumor progression. To directly determine the role of DCLK1 in pancreatic tumorigenesis and its potential to mediate the oncogenic effects of K-Ras, we have developed a highly selective DCLK1 inhibitor, DCLK1-IN-1. The goals of this proposal are to test the efficacy of DCLK1-IN-1 in cellular assays and in vivo mouse models of pancreatic cancer, with the ultimate goal of translating it into the clinic for K-Ras mutant pancreatic cancer patients.
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Ryan A. Wilcox, MD, PhD
University of Michigan
Ann Arbor, Michigan
Colony-stimulating factor-1 receptor (CSF-1R) is a novel therapeutic target in the T-cell lymphomas
The T-cell lymphoproliferative disorders are a heterogeneous and poorly understood group of non-Hodgkin's lymphomas. The most common T-cell lymphoma in the United States includes a heterogeneous mix of lymphomas that lack distinguishing characteristics and, until recently, remained clinically and molecularly "unspecified". Unfortunately, most patients afflicted with these lymphomas will ultimately succumb to their disease, thus highlighting the urgent need for the identification of novel therapeutic targets. We have observed aberrant expression of a cytokine receptor (CSF-1R) in a substantial minority of T-cell lymphomas where it promotes their proliferation in a cell-autonomous manner. As CSF-1R-mediated signaling may be distinct in lymphoid-lineage cells, we have utilized a comprehensive phosphoproteomic approach to identify downstream targets of this receptor. Our objective here is to further validate and prioritize the "hits" we have identified in order to identify those targets, and the pathways they regulate, that may be most amenable to therapeutic targeting. In addition, we will perform a high throughput screen using ~5500 small molecules, including those that are clinically available, in an effort to identify those that are synthetic lethal with a clinically available CSF-1R antagonist. We anticipate that these studies will provide a strong pre-clinical rationale for further clinical development of the novel agents and signaling pathways we identify.
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Shobha Vasudevan, PhD
Massachusetts General Hospital Cancer Center
Targeting microRNAs in chemoresistant leukemia
Acute myeloid leukemia (AML) is an important blood malignancy that displays aggressive expansion and clinical resistance. Standard therapy yields short-lived remission and often leads to relapse. Resistant cells in AML are a clinically relevant subpopulation that include dormant cancer stem cells. Such cells survive chemotherapy and restore aggressive disease. A primary issue is that effectors that perpetuate such resistant, cancer cells remain uncharacterized. A second key issue is the need to identify unique markers and regulators of resistance, to discern cells that survive clinical therapy in tumors, for early detection and improved therapeutics. MicroRNAs are noncoding RNAs that control critical gene expression in cancer and provide stable, unique signatures in patient samples. MicroRNAs unique to resistant cells remain to be uncovered and provide a distinct opportunity to discriminate resistant AML from normal cells and therapeutically block resistance. The Vasudevan lab uncovered that resistant cells in cancers show a distinct gene expression profile. Their studies found that resistant cancer cells replace conventional operations with non-canonical RNA and translation mechanisms that produce critical effectors to perpetuate these resistant cells and avoid the effects of clinical therapy. These specialized mechanisms operate through key factors and distinct microRNAs that are expressed in resistant cells—which could provide unique signatures and targets in patient samples. The Vasudevan lab is developing specialized inhibitors that can block functions of microRNAs and target genes. Based on their data, they propose that resistant AML is maintained in part by distinct microRNAs, permitting synthesis of regulators that cause clinical resistance. The primary objective of their study is to characterize and therapeutically target microRNAs that contribute to clinical resistance in AML. The project will identify microRNAs and their targets in resistant AML patient samples, and analyze them, along with preliminarily identified microRNAs, as resistance markers in patient samples. A second important focus is to develop specific inhibitors against unique microRNAs and targets that are required for resistance in AML cells and patient samples, to curtail resistance. This study will reveal insights into clinical resistance, diagnostic markers for detection of resistance, and new therapeutics against resistant AML.
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