RBN-2397 – Targeting a Novel Tumor-Intrinsic Cancer Vulnerability
We are developing our lead product candidate, RBN-2397, a potent, selective and orally available small molecule inhibitor of the monoPARP, PARP7, for the treatment of solid tumors. By inhibiting PARP7 in tumor cells, RBN-2397 has been shown in preclinical studies to directly inhibit cellular proliferation and restore Type I interferon signaling to stimulate an innate and adaptive antitumor immune response.
We are currently conducting a Phase 1 dose-escalation clinical trial with RBN-2397 as a monotherapy in patients with advanced solid tumors to primarily assess the safety and tolerability of RBN-2397 as well as establish the recommended Phase 2 dose. Secondary objectives of the trial are characterizing the safety profile, examining the pharmacokinetic parameters and identifying any initial signs of antitumor activity of RBN-2397.
Role of PARP7 in Cancer
Normal cells do not express high levels of PARP7. PARP7 is upregulated in response to cellular stress, including genomic instability in cancers and viral infection. PARP7 acts as a brake on the cellular stress response by negatively regulating the Type I interferon response in both contexts. During viral infection, Type I interferons are produced as part of the innate immune response which serves to inhibit viral replication through intrinsic effects on infected cells and activation of both the innate and adaptive immune systems.
Genomic instability in cancer cells can also stimulate these same stress pathways, and we have observed that PARP7 serves as a similar brake in cancer cells to block the production of Type I interferons and suppress the normal cellular stress response. Thus, expression of PARP7 enables cancer cells to escape senescence, or the loss of a cell’s ability to divide, and avoid immune detection and subsequent elimination.
By inhibiting PARP7 in tumor cells, RBN-2397 has been shown in preclinical studies to directly inhibit cellular proliferation and restore Type I interferon signaling to stimulate an innate and adaptive antitumor immune response.