Abstract Some of the most effective drugs used in the treatment of breast cancer are microtubule stabilizers. However, there are limitations to their clinical efficacy, including inherent and acquired drug resistance. All microtubule stabilizers that are currently approved for clinical use bind within the taxane pocket on β-tubulin in a reversible manner. The taccalonolides are a novel class of microtubule stabilizers that have a similar profile of microtubule stabilization as the taxanes, but circumvent drug resistance mediated by expression of drug efflux pumps, mutations in the taxane binding site, or overexpression of the βIII isotype of tubulin. We have shown that one important difference between the taccalonolides and clinically approved microtubule stabilizers is that the taccalonolides form a covalent bond to β-tubulin. This distinct interaction allows for irreversible binding, which explains their ability to avoid drug efflux mechanisms and likely belies their exquisite potency in in vivo antitumor models which allows for delivery in aqueous solvents. Serum stability and binding studies, microsomal clearance and pharmacokinetic analysis were performed with both taccalonolides AF and AJ to more fully understand the properties of this class of compounds. We found that both taccalonolides had low microsomal intrinsic clearance rates with no evidence of serum binding and had half-lives similar to paclitaxel in vivo. Like other microtubule targeted agents, taccalonolide AF has a narrow therapeutic window with antitumor effects accompanied by body weight loss. Interestingly, direct injection of taccalonolide AF into a xenograft tumor was highly effective with no associated toxicities at low doses, indicating that targeted delivery to the tumor would greatly increase the efficacy and decrease toxicities. To this end, efforts to promote the targeted delivery of taccalonolide AF to the tumor are being evaluated. Citation Format: Risinger AL, Li J, Benavides R, Kuhn JG, Mooberry SL. The taccalonolides are novel microtubule stabilizers that covalently bind tubulin and have in vivo efficacy in drug resistant tumors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-07.
Abstract Background: We conducted a multicenter, randomized open-label phase II neoadjuvant study of trastuzumab-emtansine (T-DM1), Lapatinib (L) and Nab Paclitaxel (Nab-P) compared to standard of care (SOC) Paclitaxel (Pac), Trastuzumab (T), and Pertuzumab (P) in patients with HER2 over-expressed breast cancer. Methods: Patients in the experimental arm received a biologic window of targeted therapies alone for 6 weeks (T-DM1 and L) followed by T-DM1 3.0 mg/kg Q3W, L 750mg oral daily and Nab-P 80 mg/m2 weekly (QW) X 12 weeks. Patients in SOC arm received targeted therapies alone for 6 weeks (T and P) followed by Pac 80mg/m2QW, T 2mg/kg QW, and P 420mg Q3W X 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or 1. Key secondary objectives included correlative assessments of PIK3CA mutations, PTEN expression, and HER2 subtypes which are being reported. Results: Thirty of the 33 enrolled patients were evaluable. Patient demographics were well balanced. HER2 subtypes and altered PIK3CA (low PTEN or PIK3CA mutations) pathway were not statistically different between both arms. We have previously reported that all patients achieved RCB 0 & I in the T-DM1, L and Nab-P arm, compared to SOC (100% vs. 62.5%, p 0.0035). In the SOC arm, the 6 week change in tumor size on breast MRI during targeted biologic window treatment is significantly different between the responders and non-responders based on two-sided Wilcoxon rank-sum test (p =0.0065). Consistent with literature, among ER positive patients treated with SOC, PTEN low expressers were less likely to respond (0%, 0 of 2) than PTEN high expressers (67%, 2 of 3). In the experimental arm, all patients responded regardless of PTEN. There was only 1 PIK3CA mutation on the experimental arm where all responded. Table 1:Breast MRI Tumor Size Standard of Care ArmResponseNMeanStandard Deviation95% CL MeanMinimumMaximumNo6-0.13330.4457-0.60110.3344-1.00.3Yes52.58001.88330.24154.91850.24.9Sixteen patients total were present in standard of care arm but 5 had incomplete imaging data. Conclusions: TDM1 plus L and Nab-P therapy was well tolerated with noteworthy responses in all patients, including in PTEN low expressers. Change in tumor size at 6 weeks of biologic therapies was significant between responders and non-responders and can be evaluated as a surrogate for future studies. Citation Format: Creamer SL, Patel TA, Ensor JE, Rodriguez AA, Niravath PA, Darcourt JG, Kaklamani VG, Meisel JL, Li X, Zhao J, Kuhn JG, Rosato RR, Qian W, Belcheva A, Boone T, Chang J. Care 001: multi-center randomized open-label phase II trial of neoadjuvant trastuzumab emtansine (T-DM1) in combination with lapatinib and nab-paclitaxel compared with paclitaxel, trastuzumab and pertuzumab in HER2-neu over-expressed breast cancer patients (TEAL study) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-26.
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