David J. Shapiro

Identification and use of small molecule biomodulators as novel anticancer drugs and probes for new regulatory pathways: ErSO, a novel small molecule biomodulator uses our recently unveiled pathway to eradicate advanced breast, ovarian, endometrial and other types of cancer.

More than 90% of cancer deaths are due to metastases, or spread, of the cancer. Nearly all metastatic cancers are incurable and most patients die within a few years. Therefore, our goal is to use our expertise in genome-wide CRISPR Screens with Negative Selection, high throughput screening, cell line development, 3-dimensional cell culture, endocrinology and animal models to identify new pathways in cancer, and small molecules that target them. From a program with Chemistry Professor, Paul Hergenrother, we identified a novel small molecule, ErSO, that often induces complete regression without recurrence of large, therapy-resistant breast tumors and of lung, bone, and liver metastases. Moreover, ErSO is also highly effective in mouse xenograft models of several other major cancers and in samples from breast and ovarian cancer patients.  ErSO’s unprecedented activity against advanced primary and metastatic cancers is achieved by exploiting our finding that estrogen-estrogen receptor (ER) activates an extranuclear tumor-protective, signaling pathway, termed the anticipatory unfolded protein response (a-UPR). We repurposed this tumor protective pathway by targeting it with ErSO. ErSO kills cancer cells by inducing lethal hyperactivation of the a-UPR, triggering rapid necrotic cell death. This game-changing turn-on strategy contrasts with widely used inhibition strategies.

A Pathway for Anticancer Therapy Induced Necrotic Cell Death

    Although immunotherapy has transformed cancer therapy, it mostly fails against solid tumors. One way to enable immunotherapy is to couple it with agents that kill cancer cells in a way that activates immune cells. Unlike apoptosis and autophagy inducers, which usually do not activate immune cells, ErSO kills cancer cells by inducing immune-cell-activating necrosis. But necrosis lacked protein markers, limiting development of targeted therapeutics. From a Genome-wide CRISPR-Cas9 Screen with Negative Selection against our necrosis inducing drugs, we identified the key executioner protein in anticancer therapy induced necrosis. Notably, four unrelated necrosis inducing cancer therapies also work, at least in part, through this pathway. Additional pathway components have been identified; unveiling the necrosis pathway, targeting it therapeutically and using it to enhance immunotherapy are areas of current and future investigation.