Breakthrough: WP1066 inhibits PD-L1 as well as STAT3
HOUSTON—Moleculin Biotech Inc., a clinical-stage pharmaceutical company focused on the development of oncology drug candidates, all of which are based on license agreements with the University of Texas system on behalf of the MD Anderson Cancer Center, announced in early December that its own sponsored research has now confirmed a recently published study demonstrating the ability of Moleculin’s clinical-stage immuno-stimulating STAT3 inhibitor, WP1066, to inhibit a key immune checkpoint target known as PD-L1.
“We have known for some time that WP1066 had the potential to stimulate a natural immune response,” said Dr. Donald Picker, Moleculin’s chief scientific officer. “But, this data suggests that our drug may be capable of having a major impact on the field of checkpoint blockades. With this information, combined with findings from other recently published studies demonstrating the important role of STAT3 in cancer immunology, we plan to run additional in-vitro and in-vivo studies, some of which are already underway, with WP1066 in combination with well-known checkpoint inhibitors to gather more data on this response.”
Added Walter Klemp, Moleculin’s chairman and CEO: “This potential was initially reported in a 2017 Japanese study (Journal of Clinical and Experimental Hematopathology, vol. 57 no.1, 21-25, 2017), but we have now been able to confirm this activity with our own sponsored research at MD Anderson. Also, very recent independent research (Front Pharmacol. 2018 May 22;9:536. doi: 10.3389/fphar.2018.00536. eCollection 2018.) has linked STAT3, HIF1-a and c-Myc (all targets of WP1066) to the mechanism (a ligand known as PD-L1) believed to be largely responsible for resistance to current checkpoint blockade therapies. We believe this could put WP1066 center-stage in the field of immunotherapy. It’s potentially a tremendous breakthrough for our company.”
Back in September, Moleculin Biotech initiated a Phase 1 clinical trial of WP1066. The compound has been shown in animal models to both inhibit an important cell signaling protein STAT3 that is involved in cell growth and proliferation and considered critical to tumor development, while also stimulating an immune response.
The first glioblastoma patient received the initial doses of WP1066, which were apparently well tolerated, in the physician-sponsored IND (investigational new drug) study at MD Anderson Cancer Center.
With the support of extensive preclinical studies demonstrating high antitumor activity and the critically important ability to cross the blood-brain barrier, in this trial WP1066 will focus on treating aggressive brain tumors, which all share a grim prognosis. The intent is to eventually treat up to 15 relapsed brain cancer patients over six to eight months, exploring safe and well-tolerated doses, as well as evaluating initial signals of effectiveness. Each treatment is completed over three weeks.
“Treating the first brain tumor patient with WP1066 is the start of a very exciting and encouraging program for doctors treating the worst types of brain cancers. There has been very little progress in recent years toward improved therapies for glioblastoma and other aggressive primary or metastatic brain tumors. WP1066 has shown extremely promising results based on animal studies where we have seen inhibition of tumor growth and improvements in survival,” said Dr. Sandra Silberman, a world-renowned oncologist and Moleculin’s chief medical officer, in the September press release.
“This is based on the fact that although STAT3 has long been identified as an important target for treating tumors, for years most efforts have focused on attempts to indirectly inhibit STAT3 from upstream signaling, not from within the cancer cell itself,” Silberman added. “WP1066 appears to be unique in its ability in-vitro and in animal models to consistently and directly inhibit the activated form of STAT3 and produce significant anticancer effects, including tumor growth inhibition and increased lifespan of treated animals.”
According to Moleculin’s website, “By inhibiting the presence of p-STAT3, WP1066 directly attacks tumor cells, as has been demonstrated in numerous preclinical tests involving a wide range of tumor cells. We believe the effectiveness of WP1066 is not only the result of attacking tumors directly, but also indirectly by stimulating the immune system, increasing the patient’s natural ability to fight off tumor development. STAT1 is believed to stimulate T cell activity and thereby the immune system responsible for fighting tumors. WP1066 has been shown to increase the activity of STAT1 at the same time it inhibits the activity of p-STAT3.”
“Although the industry has been struggling to find a way to target STAT3, we at Moleculin believe that most of these efforts have been mechanistically misguided and ended in failure because their approach would ultimately be ineffective at adequately blocking the activation of STAT3 and lack the necessary drug-like properties to succeed,” Klemp pointed out. “The opportunity to test a unique STAT3 therapy in these patients is significant in supporting Moleculin’s mission to provide benefit for those who need new and better treatments.”