Yogen Saunthararajah, MD

Taussig Cancer Institute

ALL CANCER TYPES

Pilot Award

First-in-Class Inhibitor of the ISWI Epigenetic Enzyme Family for Non-Cytotoxic, p53-Independent Oncotherapy

Drugs that stop cancer growth without harming normal cells are needed to improve safety/gentleness and effectiveness of therapy (most present cancer therapies do unfortunately harm normal cells). Identifying broad, consistent differences between growing cancer and normal cells can serve this goal: one such difference is reliance by cancer cells on classes of enzymes that turn genes ‘off’ (repressing epigenetic enzymes) to hinder their transition to non-dividing specialized cell states – inhibiting these enzymes releases cancer cells to these specialized states wherein the focus is on specialized functions rather than growing and dividing – the intended normal role underlying existence of the cancer cells in the first-place. Unfortunately, there is presently only one class of drug (DNMT1-inhibitors) that can inhibit these enzymes without undesired side-effects, but these agents have poor pharmacology that undermines their treatment potential. Thus, new, non-toxic drugs to inhibit epigenetic repressing enzymes are needed: we identified the ISWI family of epigenetic enzymes as having a central role in preventing cancer cell transition to specialized fates, but no drugs to inhibit these enzymes were available. We therefore screened small molecule libraries and found a molecular scaffold, that we modified further into a promising lead molecule active against chemo-resistant leukemia in the body without toxicity to normal growing cells. We will use Velosano support to continue our medicinal chemistry campaign toward having a new drug that does not rely on causing stress/injury, but instead uses recent understanding of mechanisms underlying cancer, to selectively stop cancer, but not normal growing cells.

IN OTHER WORDS

We want to learn how can we stop cancer cells from growing, but at the same time simultaneously spare the growth of normal cells that keep us healthy. We want to understand the underlying science to help us create better cancer treatments for the future.