Doernbecher Children's Hospital

Monika Davare Pediatric Research Lab

Overview

Our broad research objectives are to discover cell intrinsic pathways that promote oncogenesis and malignant progression of tumors, with a special interest in rare but aggressive pediatric and adult tumors like sarcoma, glioblastoma and medulloblastoma. Concomitantly we identify and test effective, targeted pharmacological agents that are amenable for clinical implementation as cancer treatments. Associated efforts to pre-emptively identify mechanisms of clinical resistance and discovery of second-line therapies have permitted us to successfully bridge bench research to clinical trials (PMID 26673800). We are also attempting to innovate approaches to target tumor immune-evasion mechanisms to enable combination therapies in genomically complex cancers that do not respond to monotherapy with kinase inhibitors. In the midst of this translational research, we hope to unravel novel molecular insights into mechanisms of cellular signaling in both normal and malignant cells, particularly for those genes whose function is poorly characterized.

Research projects

We have an overarching interest in elucidating the biological role and biochemical regulation of ROS1 in cancer cells as well as normal human cells and tissues. ROS1 remains somewhat of an enigma; as a receptor tyrosine kinase with the largest extracellular domain in the human kinome, its ligand or ligands remain unknown. Given this orphan status and sparse expression, its role in human cells and tissues is not well established. In addition, we are investigating the functional impact of ROS1 missense mutations, truncations, or overexpression or alternative splice variants in driving cancer cell phenotypes, either alone or concurrent with loss of tumor suppressor genes. To address these questions, we are using several approaches, including structure-functional analysis, loss- and gain-of-function assays, as well as pharmacological inhibition. Some ongoing projects in the lab are:

  • Functional impact of somatic ROS1 aberrations discovered in cancer patients
  • Effectively targeting ROS1, NTRK, and ALK fusion proteins in cancer
  • Pre-emptive prediction of resistance to targeted therapy in ros1 driven cancers
  • Role of ROS1 in glioblastoma
  • Discovery of novel compounds to target Ewing's sarcoma
  • Physiological regulation of and by ROS1 in normal human cells