Pre-clinical assessment of the co-operative effects of Trastuzumab and Panobinostat in HER2 overexpressing breast cancer
AffiliationSir Peter MacCallum Department of Oncology
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr. Mikolaj Medon
The introduction of Trastuzumab (Herceptin®)-based chemotherapy combinations into standard clinical practice has revolutionized the treatment of human epidermal growth factor receptor 2-positive (HER2+) breast cancer. However, less than 35% of HER2+ breast cancers demonstrate initial response to anti-HER2-based combination therapy. Of those patients with metastatic disease, who initially respond to treatment, 70% will relapse within a year of treatment initiation. These statistics continue to challenge researchers and clinicians towards a better understanding of the fundamental mechanisms of Trastuzumab action and the development of new treatment options to enhance and/or prolong its therapeutic activity. In vitro, histone deacetylase inhibitors (HDACi) have been shown to potentiate the anti-tumour effects of HER2-targeted therapies and are being trialed in combination with Trastuzumab for the treatment of patients with locally advanced HER2+ breast cancer, with promising success. The principal aim of this thesis is to provide important insights into the unique ability of the recently FDA-approved HDACi Panobinostat to promote and/or complement the cytostatic and/or cytotoxic actions of Trastuzumab, in models of primary and secondary HER2+ breast cancer. This thesis is structured around three aims which include: (i) Characterise the tumour-intrinsic and extrinsic mechanism(s) of cooperation between Trastuzumab and Panobinostat, and their capacity to evoke durable anti-cancer responses against Trastuzumab-refractory HER2+ disease. (ii) Identify molecular and/or immune signatures predictive of therapeutic response to Panobinostat and Trastuzumab co-treatment. (iii) Establish patient derived breast cancer xenografts to evaluate the potential clinical efficacy of the combination therapy The work presented demonstrates for the first time the potent and unique ability of Panobinostat to augment the cytostatic and cytotoxic actions of Trastuzumab and evoke durable, curative anti-cancer responses against established HER2+ breast tumours. In Trastuzumab-sensitive HER2+ tumours, the curative activity of the combination therapy was not dependent on an intact immune system. Tumour intrinsic mechanism of synergy between Panobinostat and Trastuzumab were dominant in this setting. Notably in these tumours the combinatorial effects of Panobinostat and anti-HER2 therapy were superior to the tumour growth inhibitory effects of conventional chemotherapy and anti-HER2 therapy. More importantly in Trastuzumab-resistant HER2+ tumours, the curative activity of Panobinostat and Trastuzumab co-treatment was dependent on an intact immune system. In these tumours, Panobinostat positively influenced Trastuzumab-mediated tumour cell clearance by promoting NK cell dependent ADCC. These data provide compelling evidence that the combinatorial effects of Panobinostat and Trastuzumab can be effective in the relapsed/refractory setting of HER2+ breast cancer, a key area of unmet medical need.
KeywordsTrastuzumab; HER2 breast cancer; Panobinostat
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