Development of a potent and highly brain-penetrable antimitotic agent SEAK193 to treat breast cancer brain metastasis

Project Abstract: Brain metastasis is one of the most common sites where breast cancer metastasizes. Despite the recent significant advances in the treatment of primary tumors, the incidence of breast cancer brain metastases (BCBMs) has increased. This increase is most likely due to improved patient survival and thus time for cancer cell dissemination, the limited efficacy of primary tumor therapies in treating BCBMs, the selection of chemoresistant metastatic clones upon treatments, and the lack of drugs that penetrate the blood-brain barrier (BBB). Compared with other major metastasis sites (bones, liver, and lungs) where the quality of life (QofL) is still manageable to some extent, patients with BCBMs have much more severe impairments in QofL and significantly lower survival. Therefore, there is a significant unmet medical need to develop an effective treatment for patients with BCBMs. Our NCI-supported research has led to the discovery and patenting of SEAK193 that: (1) has a clear mechanism of action confirmed by X-ray co-crystal structure and other experimental data; (2) has excellent metabolic stability and PK profiles; (3) is potent against drug-resistant breast tumor models in vivo; (4) has high brain penetration and shows good efficacy in an aggressive, clinically relevant taxane-refractory (TxR) BCBM TNBC PDX; and (5) shows a promising ability to potentiate anti-PD-L1 immunotherapy, which could enhance inhibition of extracranial metastases. SEAK proposes in this STTR Phase 1 to further de-risk SEAK193 as a single agent to assess its viability as a clinical candidate not only for the effective treatment of BCBMs, but also for brain metastases from other cancer types (lung, melanoma) or primary brain tumors (glioma). Aim 1. Determine the Kp,uu,brain value of SEAK193 in rats to confirm and quantify its brain penetration. SEAK193 has high brain penetration in mice. The BBB in rats more closely approximates the humans. Thus, we will confirm and quantify brain penetration of SEAK193. Milestone (1): SEAK193 has a Kp,uu,brain ≥ 0.5 in rats. Aim 2. Evaluate the efficacy of SEAK193 in two representative models of TNBC and HER2+ BCBM and assess the potential of SEAK193 benchmarked to a standard-of-care (SOC) drug, capecitabine. We will determine the efficacy of SEAK193 in the previously validated HCI-10 TNBC PDX and in the JIMT HER2+ BCBM models, which have been shown to reproducibly produce BCBMs in NSG mice. We will use capecitabine (CAPE) as the SOC reference control. Milestones (2): SEAK193 shows comparable or better efficacy vs. CAPE in suppressing BCBM growth; (3): SEAK193 therapy results in comparable or better survival ratios vs. CAPE. Aim 3. Determine the safety and comprehensive ADME profiles of SEAK193 to further de-risk SEAK193 to support future IND-enabling studies. We will first determine the safety of SEAK193 using SafetyScan47. We will also comprehensively assess its ADME properties and other safety profiles. Milestones (4): SEAK193 has negligible off-target effects; (5): SEAK193 has acceptable ADME and safety properties. Phase II plans. We will perform IND-enabling studies for SEAK193 in Phase II.