My laboratory aims to address the unmet medical need of more effective treatments for pancreas cancer patients by developing new treatment approaches. The American Cancer Society estimates 53,070 new cases and 41,780 deaths from pancreatic cancer in the United States during 2016 and predicts that pancreatic cancer will rank 2nd of all cancer-related mortalities by the year 2030. Up to 90% of pancreatic cancer patients succumb to the disease within the first year of diagnosis. Neither current chemotherapy nor molecular therapy provides patients with an extension of survival measured by more than a few months. Scientific achievements with regard to the pursued drug development projects in the last year include: 1. Preclinical and clinical development of metarrestin. Metarrestin is a novel small molecule inhibitor with selective activity against the metastatic phenotype of cancer cells. It has impressive activity in pancreatic cancer metastasis models. The drug development project 'Metarrestin, a new approach towards metastasis' was accepted into the BrIDGs program of NCATS to support IND enabling studies and clinical translation towards first-in-human studies. Work to-date identified that metarrestin has a relatively long half-life, a moderate risk of tissue accumulation in multiple species, a manageable toxicity profile with neurotoxicity as dose-limiting toxicity in large animals currently, and is likely to be given at less than daily schedules at a dose range of 0.1 to 0.5mg to humans. Additional work defined a human formulation of the drug, affirmation of stability, as well as possible back-up candidates including repurposed drugs. Preclinical work identified cancer-specific perturbations of translation and ribosomal biogenesis as novel mechanisms of action induced by the drug. 2. Preclinical development of the 'biosimilar' anti-cancer peptide RP-182. The discovery of the strong anti-cancer activity of RP-182 in murine pancreatic tumors in our laboratory has led to a patent filing of such peptides as novel effective treatment of cancers (Int'l PCT Patent Application No. PCT/US15/55305). A bioanalytical method to measure such synthetic short HDPs in complex biological specimens has been developed and filing of an Employee Invention Report (EIR) and patentation is awaited. RP-182 binds CD206 and targets CD206 positive M2 tumor-associated macrophages increasing intratumoral immunity through reduction and reprogramming of this generally immune suppressive immune cell population. RP-182 suppresses innate immune suppressive cues in pancreatic cancers acting as a 'biosimilar' (to mannose moeities of bioorganisms recognized by CD206 mannose-binding receptors on macrophages) and inducing death and reprogramming of CD206 positive immune cells in these tumors. In addition to studies targeting the CD206 axis of the innate immune system with RP-182 as part of anti-cancer combination immunotherapy approaches, there have been a number of RP-182 derivatives synthesized to improve biodistribution of RP-182 through future attachment of PEG or amino-carbon linkers, the generation of cyclic peptides, or nanocapsulation. These derivative scaffolds together with a large series of CD206 biosimilars derived from structure activity relationship are currently undergoing preclinical testing. 3. Extensive preclinical work in transgenic animals with pancreas cancer has shown that TGFbeta inhibition and gemcitabine cooperate to mediate anti-cancer immune T cell responses in murine pancreatic cancer models leading to suppression of tumor growth as well as extension of survival. This work identified upregulation of the immune checkpoint PD-L1 as one of the resistance mechanisms of this approach. The objective of the clinical protocol 'A Phase IB/II Single-arm Study of M7824 (MSB0011359C) in Combination with Gemcitabine in Adults with Previously Treated Advanced Adenocarcinoma of the Pancreas' is to test the concept of dual TGFbeta PD-L1 inhibitor (via M7824) in combination with gemcitabine now in the clinic. 4. A 20-patient phase II pilot treating patients whose tumors harbor G12R KRAS isoform somatic variants has been opened (NCT03040986; Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations) as a multiinstitutional study as part of NCIs Experimental Therapeutics Clinical Trials Network (ETCTN). The study tests the hypothesis whether KRAS G12R mutational isoforms (present in about 15 percent of pancreas cancer patients) represent an integral biomarker for response to anti-MEK therapy as novel therapy in 2nd line treatment of pancreas cancer. This clinical study is a direct translation of our laboratory findings of increased sensitivity of KRAS G12R mutational isoform-harboring cell lines and patient-derived xenotransplantation models. 5. Preclinical development of the stem cell inhibitor -8382. The scientific goal of this program developed in my laboratory is to show selective anti-cancer stem cell activity of this small molecule inhibitor, which effectively suppresses stemness and metastasis formation, in comparison to gemcitabine chemotherapy in cell-based and in vivo assays of stemness. A series of spheroid clonogenicity assays, in vivo tumor initiation studies, and measures of stemness using flow cytometry including side population (SP) profiling experiments confirm a selective anti-cancer stem cell function of the inhibitor compared to gemcitabine. Thousand-and-one amino acid protein kinase 3 (TAOK3) involved in regulation of the HIPPO pathway, a known signaling network regulating self-renewal and stemness, emerged as a novel anti-cancer target justifying drug development efforts against this class of kinases previously not known to be involved in pancreatic cancer development and progression.
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