Targeting brain and bone metastases in metastatic breast cancer for improved patient survival

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A major clinical challenge in breast cancer is to prevent and to treat metastatic disease. Two key hurdles for therapies for metastatic breast cancer (MBC) patients are to treat brain metastases (BrnMets) and to prevent progression of bone metastases (BonMets). Chemotherapeutic drugs, including the taxanes, remain mainline therapies for stage IV patients with MBC. However, prolonged clinical use of taxanes is associated with development of multidrug resistance, dose-limiting hematopoietic toxicity, and neurotoxicity. Our ongoing efforts in this area has led to an investigational new drug, Sabizabulin. Use of Sabizabulin in MBC and other tumor models demonstrated suppression of primary tumor growth and tumor metastasis, and effectiveness in overcoming taxane resistance. Since Sabizabulin has limited brain penetration, its further modification led to the discovery of SB-216, a highly brain penetrable analog that has excellent efficacy in multiple taxane-resistant tumor models. To further develop the SB-216 scaffold for MBC, the goals of this project are to: (1) perform focused structural optimization based on the SB-216 scaffold to produce new potent and high brain penetrable analogs that can overcome taxane resistance for MBC BrnMets management; and (2) develop novel drug conjugates with bisphosphonate (BisPhos) for MBC bone BonMets treatment. AIM 1. Perform focused structure-based optimization based on the SB-216 scaffold to develop new analogs with high brain penetration ability. Crystal structures of tubulin/SB-216 complexes will be used to guide focused, iterative lead optimization. We will screen new analogs in vitro using a panel of MBC cell lines, including cells derived from PDX models, and normal cells. We will determine their brain penetrations to select the ten best compounds for in vivo efficacy studies. AIM 2. Determine the in vivo efficacy of selected SB-216 analogs for suppressing MBC BrnMets. We will first determine the maximum tolerable dose and pharmacokinetics for selected SB-216 analogs from Aim 1 to identify the overall best three analogs for in vivo evaluation using multiple well-characterized, pre-clinical models of MBC, including taxane-refractory models, each with pre-existing BrnMets to score for delay of metastatic progression. AIM 3. Conjugate Sabizabulin, SB-216 and its new analogs with BisPhos for more efficacious targeting of MBC BonMets, using the best Sabizabulin conjugate and paclitaxel as the references. Conjugating Sabizabulin, SB-216, or its new analogs with a BisPhos drug with very high affinity to bones will increase the efficacy of treating BonMets. Thus, we will optimize the linker chemistry and evaluate a variety of BisPhos drugs for conjugation. Conjugates will first be evaluated in vitro for stability and activation to select the two best conjugates for further in vivo efficacy studies using BonMet pre-clinical models. Impact: The addition of a new generation of tubulin inhibitor to the existing panel of chemotherapeutic drugs is likely to improve MBC patient PFS, OS and QOL. In addition, patients diagnosed with other types of metastatic solid tumors in which tubulin inhibitors are currently standard of care (SOC) could also benefit from this project.