Targeting tumor repopulation and the immune microenvironment to overcome chemoresistance

PROJECT SUMMARY
This application is in response to PAR-19-183: Biology of Bladder Cancer. Muscle invasive bladder cancer
(MIBC) claims approximately 18,000 deaths annually in the United States. Funding and research devoted to
this cancer-type are significantly under-proportioned. An unmet clinical need for MIBC treatment lies in the
poor patient response towards chemotherapy, with treatments providing only a dismal 5% improvement in
overall survival. The long-term goal of this application is to address this urgent need for adjuvant therapies
to improve chemotherapeutic response. The success of chemotherapy is historically thought to solely depend
on its direct cytotoxic effects on tumor cells. However, there is growing evidence, as shown by our own
research and others, that chemotherapeutic efficacy is also dependent on 1) successful prevention of cancer
stem cells in repopulating residual tumors and 2) an effective anti-tumoral immune response. These two
phenomena are often investigated separately but their possible synergy has been overlooked. Our research
project is conceptually innovative to examine a common upstream pathway that regulates both tumor
repopulation and immune response. We hypothesize that the inhibition of this common pathway will provide
an effective therapeutic target for clinical translation. Our specific aims include: Aim 1) Decipher this pathway
by investigating the non-canonical downstream mechanism leading to the extracellular release of pleiotropic
factors. This is significant, since these extracellular factors can modulate both tumor repopulation and
immune response. Aim 2) Evaluate how these extracellular factors and their cognate receptors drive the
repopulation of quiescent cancer stem cells. Aim 3) Investigate how inhibition of this upstream pathway can
collectively abrogate tumor repopulation and immunosuppression, and thus, enhance chemotherapeutic
response. Success of this proposal will pose drug targets capable of augmenting patient response to
chemotherapy. Moreover, these findings will provide insights to how these drugs can reestablish an
immunostimulatory tumor microenvironment in MIBCs. In summary, the studies outlined in this proposal are
significant to address an unmet need, i.e., to improve a dismal response of MIBC patients to standard
chemotherapy. The conceptual advance from this study will likely extend beyond MIBC to benefit patients
from other epithelial malignancies.

Grant Number: 5R01CA255609-06
NIH Institute/Center: NIH
Principal Investigator: Keith Syson Chan