Synthetic Lethality Pipeline

Overview

We are actively pursuing the discovery and development of small molecule inhibitors of a number of targets based on synthetic lethality. Our pipeline in synthetic lethality comprises multiple preclinical programs against both known and novel targets, which is complemented by a robust target discovery platform. Synthetic lethality occurs between two genes when the loss of function of either gene alone does not affect cell viability, but the simultaneous loss of function of both genes leads to cancer cell death. We believe these programs may have a higher likelihood of demonstrating efficacy because the biological hypothesis of synthetic lethality can be tested preclinically, and each synthetic lethal target that we expect to pursue will have a clearly defined tumor-associated biomarker for patient selection.

Although mutated, amplified, and deleted genes in cancer have been catalogued, only a fraction of such genes are amenable to conventional drug discovery approaches. A subset of historically undruggable targets can potentially be pursued indirectly, based on the concept of synthetic lethality. For example, cancer cells with loss of function mutations in a tumor suppressor gene “A” may have susceptibility to pharmacological inhibition of its synthetic lethal partner, gene “B”. In this context, the drug target can be gene “B” and the biomarker for defining the clinical population can be based on detection of a mutation in gene “A”.

Our pipeline in synthetic lethality includes programs targeting:

  • MAT2A, in tumor cells having MTAP gene deletion, which occurs in approximately 15% of all solid tumors;
  • Pol-theta, in tumors with genetic mutations in HRD, including BRCA mutations which occur, for example, in approximately 14% of ovarian cancer tumors;
  • PARG, in tumors with genetic mutations in base excision repair, the prevalence of which is being evaluated in several solid tumors; and
  • WRN, in high MSI tumors, present for example, in approximately 15% of colorectal cancer tumors.

MTAP-null cells lack the ability to metabolize 5-methylthioadenosine, or MTA, which is an essential step in a biochemical pathway involved in salvaging metabolite S-adenosyl methionine, or SAM. Increased levels of MTA partially inhibit the methyltransferase PRMT5 for which SAM is the substrate. This partial inhibition renders MTAP-null cells more dependent on the activity of methionine adenosyltransferase II alpha or MAT2A, an enzyme that is responsible for the synthesis of SAM. Because of this dependence, loss of MTAP results in synthetic lethality when MAT2A is pharmacologically inhibited.

MTAP deletions are prevalent in approximately 15% of all human tumors across various tumor types. Genetic profiling tests for the deletion of MTAP or for the commonly co-deleted gene CDKN2A are commercially available.

Prevalence of MTAP Deletions in Selected Indications

Source: TCGA Data in cBioportal

Pol-theta is involved in a DNA repair process called microhomology mediated end joining, or MMEJ, that is utilized when homologous recombination mediated repair is compromised, as happens in the case of BRCA1 or BRCA2 mutations. The expression of Pol-theta is largely absent in normal cells, but tumor cells harboring double strand break repair defects, such as BRCA1 or BRCA2, show synthetic lethality when Pol-theta is knocked down with RNA.

Prevalence of HRD in Solid Tumor Types

Source: Heeke et al., JCO Precis Oncol. Sep 2018

MSI is a change in the DNA content of a tumor cell in which the number of repeats of microsatellites, short repeated sequences of DNA, differ as cells divide. High MSI is present in many solid tumor cancers, and tumors are routinely assessed for MSI status in multiple diagnostic profiling tests.

WRN protein is a RecQ enzyme involved in the maintenance of genome integrity. Germline loss of function mutations in WRN lead to premature aging and pre-disposition to cancer. We have evaluated synthetic lethality between WRN and high MSI.

WRN is a protein having several functional domains, and we have shown that the helicase functional domain of WRN is responsible for this synthetic lethal interaction in MSI-high cells. We recently published this work in Cell Press – iScience, Werner Syndrome Helicase is Required for the Survival of Cancer Cells with Microsattelite Instability,Vol. 13, pp. 488-497 (Mar 2019).

Prevalence of High MSI Frequency in Solid Tumor Types

Source: JCO Precision Oncology 2017

Poly (ADP-ribose) glycohydrolase, or PARG, has demonstrated a synthetic lethality relationship with RNA knockdown of several genes encoding proteins involved in the terminal steps of BER

PARG functions as a regulator of DNA repair in the same biochemical pathway as PARP. In particular, PARG hydrolyzes poly (ADP-ribose), or PAR, chains that are polymerized by PARP enzymes.