Enhancing the Cytotoxicity of T-DM1 to Treat HER2+ Breast Cancer
Posted April 7, 2020
Joan Brugge, Ph.D., Harvard Medical School
Jason Zoeller, Ph.D., Harvard Medical School
Overcoming drug resistance is a major hurdle in treating advanced and metastatic breast cancer. Trastuzumab emtansine (T-DM1) is an FDA-approved antibody-drug conjugate (ADC) that is designed to deliver the cytotoxic agent, emtansine, specifically to tumor cells expressing HER2 protein. While the clinical benefit of T-DM1 has been demonstrated in advanced and metastatic HER2+ breast cancer patients, tumors ultimately become resistant, causing patients’ breast cancer to progress to lethal metastatic disease. A family of anti-apoptotic proteins, B-cell lymphoma 2 (BCL-2) and B-cell lymphoma extra-large (BCL-XL), have been found to be upregulated in breast cancers and to contribute to the development of therapy resistance. With the support of a Fiscal Year 2015 Breast Cancer Research Program Breakthrough Award – Funding Level 2, Dr. Brugge and Dr. Zoeller aimed to evaluate whether BCL-2/XL inhibition by ABT-263 (navitoclax) could enhance the effectiveness of T-DM1 in HER2-expressing breast cancers.
Using five HER2-expressing patient-derived xenograft (PDX) mouse models developed from primary and metastatic breast tumors with and without prior treatment exposure, a combination of T-DM1 and ABT-263 was compared to treatment with either agent alone. Results from this study were recently published in Molecular Cancer Therapeutics and demonstrated that two of the treatment-exposed metastatic PDX-models, PDX12 and PDX8, had the most robust responses to combination therapy. Treatment with combination therapy in PDX12 and PDX8 mouse models significantly enhanced tumor killing and resulted in a reduction in tumor size compared to either agent alone. Microscopic analysis of PDX12 and PDX8 tumor sections revealed that combination treatment resulted in a dramatic reduction in the number of invasive tumor cells present, whereas single agent treatment alone had little to no effect. Tumors from PDX model BCM-3963 (treatment-naïve primary breast tumor) were responsive to T-DM1 alone, but little to no additive effect on tumor size was observed following combination treatment. However, upon microscopic analysis of BCM-3963 tumor sections, an increase in cancer cell killing was seen when T-DM1 was administered in combination with ABT-263, suggesting that ABT-263 enhanced the cytotoxicity of T-DM1.
Although BCL-2 inhibitors have shown promise in clinical trials, their use has been limited due to thrombocytopenia (platelet reduction) observed in patients. To overcome this treatment-associated side effect, the team devised a pulsed dosing regimen where ABT-263 was administered in intervals rather than continuously. T-DM1 treatment given with pulsed ABT-263 did not reduce the pre-clinical effectiveness of combination treatment in PDX12 and PDX8 tumors, and importantly, mitigated the platelet side effects associated with ABT-263.
These results demonstrate for the first time that the effectiveness of T-DM1 can be enhanced by inhibition of BCL-2/XL using an orally available and clinically tested compound (navitoclax), and provide evidence for a translational paradigm involving ADCs together with anti-apoptotic inhibitors in order to ameliorate the systemic toxicities associated with these therapies.
Pre-clinical in vivo treatment response associated with navitoclax+T-DM1 were assessed by Masson's trichrome stain and were characterized by the significant elimination of tumor cells (red) and the emergence of stromal content (blue)
Zoeller JJ, Vagodny A, Taneja K, et al. 2019. Neutralization of BCL-2/XL enhances the cytotoxicity of T-DM1 in vivo. Mol Cancer Ther. 18(6):1115-1126.
Public and Technical Abstracts: Preclinical Evaluation of BCL2/BCLXL Inhibition to Enhance the Efficacy of Antibody-Drug Conjugates (ADCs) for the Treatment of Distinct Breast Cancer Subtypes
Last updated Monday, January 3, 2022