Problem

Breast cancer (BC) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death among women in the United States. Within its subtypes, triple-negative breast cancer (TNBC) carries the highest mortality, driven in large part by a lack of effective targeted therapies. This underscores an urgent need to define novel molecular targets and develop new effective precision treatment strategies for TNBC.

Solution

• Researchers at The Ohio State University identified the RAS-like proto-oncogene RALA, a small GTPase activated downstream of RAS, as a potential therapeutic target in breast cancer. Elevated RALA expression is associated with adverse outcomes across multiple BC subtypes and is most strongly prognostic for poor survival and metastatic recurrence in TNBC. Preclinical studies in human cell lines, patient-derived xenografts, syngeneic tumor models, and genetically engineered mouse models demonstrate that TNBC growth and progression are highly dependent on RALA. Commercially available RAL inhibitors, such as RBC8 and BQU57, have been shown to equally reduce viability in both RAL-dependent and RAL-independent cell lines, suggesting off-target mechanisms rather than specific inhibition of RAL signaling.
• To overcome the limited efficacy of existing RAL inhibitors, the research team at OSU developed a novel small molecule, OSURALi. OSURALi potently suppressed RALA activation and exhibited selective cytotoxicity in RAL-dependent cell lines relative to RAL-independent lines and normal cells. In vivo, OSURALi was well tolerated in mice and significantly reduced tumor growth as well as spontaneous lung metastases in a triple-negative breast cancer model.

Applications

• Treatment of breast cancer, particularly TNBC, either as monotherapy or in combination with existing therapies. Potential synergy with immunotherapies.
• Possible application in other tumor types characterized by RALA or RALB overexpression or hyperactivation.
• Because RALs function as downstream effectors of RAS, OSURALi may provide a strategy to inhibit RAS-driven signaling across diverse cancers.

Advantages

• On-target activity: Unlike existing RAL inhibitors, OSURALi-induced cytotoxicity aligned with the intrinsic RAL dependency of cell lines, demonstrating that its antitumor effects are mediated through specific inhibition of RAL signaling.
• Selectivity for TNBC: OSURALi exhibited preferential cytotoxicity towards TNBC cell lines compared to normal cells and was well tolerated in vivo, suggesting reduced risk of systemic toxicity and side effects.

Seeking opportunities for out-licensing and collaboration