Patients diagnosed with advanced pancreatic ductal adenocarcinoma (PDAC) have a 5 year survival rate of less than 5%. These tumors have the highest reported incidence of KRAS mutations among all human cancers. Because of these observations, there has been considerable interest in developing direct inhibitors of RAS mutants such as KRAS. However, attempts to directly inhibit KRAS have to date been unsuccessful. An alternative approach is to target downstream effectors of KRAS on the MAPK pathway. Extracellular Regulated Kinase 1 and 2 (ERK 1/2) are serine-threonine protein kinases which are downstream components of the RAS/RAF/MEK signal transduction pathway. Aberrant activation of ERK has been demonstrated in many human tumors, including pancreatic cancer. ERK inhibitors could prove very useful as therapies to treat tumors with RAS mutations such as PDAC. This proposal aims to determine the potential of Kalyra's novel ERK inhibitors as treatments for PDAC via the following aims. Phase 1: Characterization of Novels Leads in Models of Pancreatic Cancer Aim 1. Evaluate 10 lead molecules in preliminary in vitro ADME and Plasma Protein Binding studies. Aim 2. Confirm efficacy of 5 lead molecules vs. a panel of human RAS mutant pancreatic cancer cell lines. Aim 3. Determine PK and in vivo efficacy of top 3 leads in an in vivo model of KRAS pancreatic cancer. Phase II: Additional studies to enable selection of a Development Candidate Aim 1. Characterize the effects of lead ERK inhibitors in combination studies Aim 2. ADME and Preliminary Toxicology Aim 3. Pharmcokinetics for Species Selection for Toxicology and Pilot Toxicology
Public Health Relevance Statement: Public Health Relevance: Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment with current standard of care. Kalyra is developing a novel orally bioavailable MAP kinase pathway inhibitor, with a new mechanism of action. Kalyra's novel inhibitors offer the potential to deliver best in class drugs for inhibiting the MAP Kinase pathway both in terms of efficacy and tolerability. These inhibitors offer the potential to effectively tret patients whose cancers are associated with activation of the MAP kinase pathway, which include those with PDAC. With lead molecules in hand, this proposal aims to conduct the non-clinical studies required to select a development candidate, with the goal of developing a novel, safe and well-tolerated therapy for the treatment of PDAC.
NIH Spending Category: Cancer; Digestive Diseases; Pancreatic Cancer; Rare Diseases
Project Terms: Abraxane; absorption; analog; Binding Proteins; Bioavailable; Biochemical; Biological Assay; Biological Availability; BRAF gene; Cancer cell line; Canis familiaris; Cardiac; Cell Line; Cessation of life; Chemistry; Clinical; Clinical Trials; design; Development; Diagnosis; Dose; drug candidate; Drug Kinetics; effective therapy; Evaluation; Exhibits; extracellular; gemzar; Goals; Hand; Health; Human; improved; In Vitro; in vivo; in vivo Model; Incidence; inhibitor/antagonist; interest; KRAS2 gene; Lead; Malignant neoplasm of pancreas; Malignant Neoplasms; MAP kinase activator; MAP Kinase Gene; MAPK3 gene; MEKs; Metabolism; Mitogen-Activated Protein Kinases; Modeling; mutant; Mutation; Newly Diagnosed; novel; Oral; pancreatic cancer cells; Pancreatic Ductal Adenocarcinoma; pancreatic neoplasm; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phosphorylation; Phosphotransferases; Plasma Proteins; preclinical study; prevent; Property; Protein-Serine-Threonine Kinases; Rattus; Reporting; Resistance; Rodent; Route; Safety; screening; Series; Signal Transduction; Signal Transduction Pathway; standard of care; Survival Rate; Time; tool; Toxic effect; Toxicology; tumor; upstream kinase
