Immunomodulatory Effects of Targeting DNA Repair with Novel Temozolomide Combinations in Colorectal Cancer

ABSTRACT
DNA repair plays an important role in the pathogenesis of virtually all cancer types, and the identification of
aberrant DNA repair pathways has identified predictive and prognostic biomarkers to targeted therapies. For
example, epigenetic hypermethylation of the promoter of O6-methylguanine DNA methyltransferase (MGMT)
predicts for better patient survival and increased sensitivity to temozolomide (TMZ) in multiple cancers,
including colorectal cancer (CRC). TMZ is a monofunctional alkylator, and the DNA damage caused by TMZ is
principally repaired by MGMT, which is silenced by promoter hypermethylation. The base excision repair (BER)
pathway also serves as a critical pathway to repair TMZ DNA damage. Preclinically, the simultaneous inhibition
of BER with polyp ADP ribose polymerase (PARP) inhibitors further sensitizes MGMT deficient tumors to TMZ.
However, our preliminary findings reveal an alternative and parallel mechanism: TMZ damage causes acute
replication stress and fork collapse leading to Ataxia Telangiectasia and Rad3 related (ATR) dependent
phosphorylation of Checkpoint Kinase 1 (Chk1). We have leveraged these findings, and additional in vivo
experiments, to advance novel TMZ combinations into the clinic with two investigator-initiated clinical trials for
MGMT silenced CRC: 1) TMZ + olaparib (PARP inhibitor) and TMZ + AZD 6738 (ATR inhibitor). Enrollment will
proceed at Yale Smilow Cancer Hospital with future opportunities expand to collaborating sites through our
CRC Stand up to Cancer (SU2C) Dream Team. Furthermore, we aim to develop new biomarker assays
including a biomarker assessing MGMT heterogeneity to identify tumors most sensitive to TMZ combinations,
and perform genomic profiling. Leveraging DNA damage additionally represents a potential tool to stimulate an
immune response, and through ancillary studies and using specimens obtained from our trials we will study the
effects TMZ combinations on the immune microenvironment to lend support to the addition of immunotherapy
in the future. I am a medical oncologist focusing on the treatment of advanced gastrointestinal (GI) cancers
with an emphasis on innovative therapies for CRC. This award will facilitate my development as a physician-
scientist equipped to design and conduct investigator-initiated early phase clinical trials based on innovative
preclinical evidence regarding DNA repair and immunotherapies. My training will include didactic coursework
for tumor immunology, practical experience of clinical trial implementation, and formal instruction in biomarker
techniques. To achieve these goals, I have assembled a multidisciplinary mentorship team led by my primary
mentor, Dr. Patricia LoRusso who has a proven track record of successfully mentoring junior faculty and
extensive expertise in investigator-initiated clinical trials. At the conclusion of this award, I will have gained
valuable skills into the underpinnings of clinical research generically, and specifically for clinical trial design,
and biomarker identification for DNA repair and immunology. This award will help establish me as an
independent investigator conducting early phase clinical trials for CRC and other GI cancers.

Grant Number: 5K08CA255465-05
NIH Institute/Center: NIH
Principal Investigator: Michael Cecchini