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 55,440 new cases and 44,330 deaths from pancreatic cancer in the United States during 2018 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 (EIR (E-276-2011) and patent application E-114-2018-0-US-01; Metarrestin (ML-246) for the Treatment of Adenocarcinoma of the Pancreas). 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 a first-in-human study at CCR. IND enabling studies are completed. The drug has an acceptable predicted therapeutic window and manufactured clinical grade metarrestin in capsule form acceptable stability for phase I clinical testing. Reports of IND enabling studies are currently awaited with an anticipated filing in Q1 2019. Preclinical work identified the translation elongation factor eEF1A2 upregulated in cancer as the molecular target of metarrestin and interference with ribosomal biogenesis as a novel mechanism 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 and human cancer models in our laboratory has led to a patent issuance of such peptides as novel treatment for pancreatic cancer (United States Patent No. 10,016,480 issued July 10, 2018; Peptide-based methods for the treatment of pancreatic cancer). A bioanalytical method to measure such synthetic short HDPs in complex biological specimens has been developed. 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. This makes RP-182 an attractive agent for immunotherapy treatment combination in immunologically 'cold' cancers which currently don't respond to T cell activation like immune checkpoint inhibition. RP-182 suppresses innate immune suppressive cues by acting as a 'biosimilar' (to mannose moeities of bioorganisms recognized by CD206 mannose-binding receptors on macrophages) and induces cell death and reprogramming of CD206 positive immune cells in these tumors. Via a novel in silico homology screen strategy a series of CD206 organic small molecule mimetics is currently undergoing testing in cell based anti-macrophage assays under the hypothesis that a small molecule retaining the selective anti-M2 macrophage killing function of RP-182 should have superior PK properties, exposure, and efficacy in vivo. New drug designs with RP-182 are being made including the coupling of RP-182 to PD-1/PD-L1 antibodies or to a scaffold in preparation of creating tripod immuno-oncology agents (coupled immunocytokines, checkpoint regulators, and RP-182 to one scaffold). 3. 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 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 testing the concept of dual TGFbeta PD-L1 inhibitor (via M7824) in combination with gemcitabine with accrual of the phase I safety run-in being completed. In addition, for locally advanced pancreatic cancer, the clinical protocol 'A Phase I/II study of the immune checkpoint inhibitor M7824 and the immunocytokine NHS-IL12 in combination with stereotactic body radiation therapy (SBRT) in adults with advanced pancreas cancer' was approved by the Scientific Review Committee of CCR. 4. A phase II pilot study treating patients whose tumors harbor G12R KRAS isoform somatic variants (NCT03040986; Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations) has not proceeded to the 2nd stage due to lack of efficacy of the selected 1st generation MEK inhibitor. This clinical study was 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 a small molecule inhibitor derived from a drug screen in pancreas cancer cells grown as spheroids. The molecule 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) 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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