Dr Flora on the Mechanism of Action of BXQ-350 in Newly Diagnosed CRC

“There are some properties of proliferation of cancer cells that S1P will promote, activating some oncogenic pathways and stimulating immunosuppressor cells. This new product can increase ceramide [levels] and reduce S1P [levels]. Ceramide is pro-apoptotic, so some of that downregulation may stimulate immune effector cells to activate things that raise ceramide levels.”

Daniel B. Flora, MD, PharmD, medical oncologist, medical director, oncology research, St. Elizabeth Healthcare, discusses the mechanism of action of thenovel sphingolipid metabolism modulator BXQ-350 and how this mechanismprovides the rationale for the agent’s investigation in combination with modified FOLFOX7 (mFOLFOX7; leucovorin, fluorouracil, and oxaliplatin) and bevacizumab (Avastin) in patients with newly diagnosed metastatic colorectal cancer (mCRC).

Sphingolipid metabolism plays a critical role in cancer biology, with ceramides and sphingosine-1-phosphate (S1P) exerting opposing effects on tumor progression, Flora begins. Ceramides promote apoptosis and mitigate chemoresistance, whereas S1P facilitates cancer cell proliferation, activates oncogenic pathways, and supports an immunosuppressive tumor microenvironment (TME), he details. As such, targeting sphingolipid metabolism represents a potential therapeutic strategy in CRC, according to Flora.

BXQ-350, a nanovesicle formulation of Saposin C, functions as an allosteric activator of sphingolipid metabolism, reducing systemic S1P levels andincreasing C18 ceramide levels, Flora explains. Preclinical data suggest that BXQ-350 selectively targets tumor cells, sparing normal tissue within the TME, he notes. This agent was initially evaluated in a phase 1 dose-escalation study (NCT02859857) in patients with advanced solid malignancies. BXQ-350 was well tolerated, with no dose-limiting toxicities or maximum tolerated dose identified. The clinical benefit rate with BXQ-350 among evaluable patients and across all 6 gastrointestinal tumor types was 17.8%, and outcomes included partial responses and stable disease. Additionally, BXQ-350 showed signs of alleviating chemotherapy-induced peripheral neuropathy (CIPN), with 1 patient with chronic CIPN at enrollment self-reporting symptomatic improvement.

Currently, the phase 1b/2 ASIST study (NCT05322590) is investigating BXQ-350 in combination with standard mFOLFOX7 plus bevacizumab in the frontline setting in patients with newly diagnosed mCRC.