Developmental Research Program

Developmental Research Program

Jean-Pierre Issa, MD

Peter Jones, PhD


The specific objectives of the Developmental Research Program are to:

  1. Publicize the availability of funds for pilot translational research studies in the field of Epigenetic Therapy for cancers.
  2. Identify through this mechanism innovative projects with significant potential for developing and improving Epigenetic Therapies for cancers.
  3. Encourage collaborations of projects with scientists within the SPORE and outside the SPORE, specifically the Van Andel Institute-Stand Up To Cancer Epigenetics Dream Team (VAI-SU2C).
  4. Enhance the communication between the SPORE leaders and VAI-SU2C Investigators to encourage the development of innovative epigenetics therapies for cancer.
  5. Ensure program flexibility so that developmental projects that show promise can be: 1) funded for a second year; 2) encouraged to apply for peer-reviewed funding (i.e. R01); or 3) expanded to become full SPORE projects.

To achieve our aims, we will establish 1) specific criteria for selection and funding through a peer review mechanism, and 2) mechanisms for close monitoring of, and collaboration between the SPORE leaders and program awardees to enhance the quality of the translational research goals.

YEAR 2 - AWARDEES

Heather M. O'Hagan, PhD

Indiana University School of Medicine

Inhibiting the lysine demethylase LSD1 to improve targeted therapy response in metastatic BRAF mutant colorectal cancer

Targeted therapy resistance can occur when cancer cells change their cellular identity so they are no longer dependent on the abnormal protein that the therapy targets. In our research we propose to use epigenetic inhibitors to block therapy-induced transformation and improve therapy response in BRAF mutant colon cancer.

Cynthia A. Zahnow, PhD

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Determination of the effectiveness of the dual G9a and DNMT inhibitor, CM272, in WT-TP53 and mutant TP53 ovarian cancers and the potential to re-sensitize PARP resistant ovarian cancers to PARP inhibition

Euchromatic histone-lysine N-methyltransferase 2 (EHMT2, also known as G9A) is a nuclear histone lysine methyltransferase that catalyzes H3K9me1 and H3K9me2 marks associated with transcriptional gene silencing.  In addition to its role in histone methylation, G9A can methylate and inactivate the tumor suppressor protein, p53 (K373me2), but the role of this inactivation mechanism in cancer has not yet been extensively explored.   Dr. Zahnow’s laboratory has preliminary evidence that CM272 is more effective in Trp53 WT vs.Trp53 mutant ovarian cancer and this one year project will seek to determine whether the mutational status of TP53  plays a role in regulating the effectiveness of the dual G9a/DNMT inhibitor, CM272 in ovarian cancer. We hypothesize that wildtype p53 protein in these tumors might be transcriptionally inactive as a result of G9a methylation.  Therapeutic inhibition of G9a via CM272 in such tumors could therefore lead to p53 reactivation and cancer cell death.

G9A also promotes DNA damage repair via recruitment of BRCA1, 53BP1, and other factors involved in homologous recombination (HR) and non-homologous end joining (NHEJ). G9a is frequently amplified and overexpressed in ovarian cancers that are resistant to PARP inhibitors (PARPi), and high G9a expression correlates with aggressive peritoneal metastasis and poorer overall survival. Disruption or elimination of G9A in PARPi-resistant cells has been shown to re-sensitize tumor cells to PARPi.  We hypothesize that CM272 may be able to re-sensitize resistant cells once again to PARP inhibitors. Our goal is to test CM272 in clinical trials for ovarian cancer within the next several years; and it is imperative that we determine whether p53 status plays a role in the effectiveness of CM272 and G9a inhibition. If so, p53 status and PARPi resistance may be key factors in patient selection.