Veterinary Science Collected Works - Theses
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ItemSensitivity of canine haematological cancers to BH3 mimetics( 2022)Background: Haematological cancers such non-Hodgkin lymphoma (NHL) and acute and chronic leukaemias are common in both humans and dogs. Whilst these cancers can be treated with cytotoxic chemotherapy (and immunotherapy in people), development of treatment resistance is common. A frequently identified mechanism associated with resistance to chemotherapy-induced cell death is overexpression of the antiapoptotic B cell lymphoma 2 (BCL2) protein. Highly specific small molecule inhibitors of antiapoptotic BCL2 proteins, known as B cell lymphoma Homology 3 (BH3) mimetics, result in rapid induction of apoptosis in vitro and in vivo in human haematological cancer cells. This has led to the approval of the BCL2-specific inhibitor, venetoclax (VEN), for the treatment of chronic lymphocytic leukaemia (CLL) and acute myeloid leukaemia (AML) in Australia, North America and Europe. Expression of BCL2 has been reported in canine nodal lymphoma, however sensitivity of primary canine cells to BH3 mimetics has not been evaluated. Objectives: This study aimed to assess the in vitro sensitivity of non-neoplastic lymphocytes and primary haematological cancer cells from dogs to VEN or the dual BCL2/BCLxL inhibitor, navitoclax (NAV). The second aim was to evaluate the association between BCL2 protein expression and sensitivity to VEN. Methods: Nine dogs without cancer and 30 dogs with haematological cancers were recruited. Lymphocytes were isolated from peripheral blood, lymph node and/or bone marrow and incubated with VEN or NAV for 24 hours. Viable cells were enumerated using flow cytometry and the half maximal effective concentration (EC50) was calculated; BCL2 protein from whole cell lysates was assessed via immunoblotting. Results: Non-neoplastic lymph node-derived B and T canine lymphocytes were more sensitive to VEN than circulating lymphocytes (P = 0.02). Eighteen dogs with haematological cancers were included in the final analysis, including six cases of non-indolent multicentric B cell lymphoma, four cases of acute leukaemia, three cases of non-indolent multicentric T cell lymphoma, two cases each of indolent T-zone lymphoma and T-cell CLL, and one case of multiple myeloma. Neoplastic T lymphocytes (7/7) showed marked sensitivity to BH3 mimetics, with an EC50 <100nM, whilst 6/7 samples of non-indolent B cell cancers were resistant to VEN, with an EC50 >1000nM. All samples of acute leukaemia showed sensitivity to NAV, however sensitivity to VEN varied. Canine BCL2 protein was detected in all samples sensitive to VEN and was variably detected in resistant samples. All samples that lacked BCL2 were resistant to VEN. Conclusion and Clinical Importance: Neoplastic canine T lymphocytes are sensitive to VEN at concentrations achievable in vivo, thus VEN may be a novel therapeutic agent for treatment of canine T cell cancers. Detection of BCL2 protein is insufficient to predict in vitro sensitivity to VEN.