mln-8237 and Lymphoma--Non-Hodgkin

Aurora kinases are essential mediators in cell mitosis. Amplification of these kinases can lead to the development of malignancy and may be associated with inferior survival. Alisertib is an oral aurora kinase inhibitor which has been shown to induce cell-cycle arrest and apoptosis in preclinical studies. It is currently under investigation for a wide variety of malignancies including hematologic (specifically Non-Hodgkin's lymphoma) and solid tumors. Areas covered: A PubMed search was performed to identify clinical studies reporting outcomes with alisertib. Promising results are notable in patients with peripheral T cell lymphoma in particular, forming the basis for the first phase 3 randomized trial of alisertib. Although it did show encouraging response rates, it failed to demonstrate superiority over the comparator arm at an interim analysis, halting further enrollment. Expert opinion: Despite disappointing early results, alisertib remains under investigation in a number of cancer types both as monotherapy and in combination with traditional cytotoxic chemotherapy, with encouraging results. Most common toxicities in early trials include myelosuppression alopecia, mucositis and fatigue. The relatively manageable toxicity profile of alisertib along with ease of dosing may allow it to be combined with other oral agents or traditional chemotherapy across a wide variety of malignancy types.

Topics: Animals; Antineoplastic Agents; Apoptosis; Aurora Kinase A; Azepines; Humans; Lymphoma, Non-Hodgkin; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Randomized Controlled Trials as Topic

Topics: Adult; Aged; Antineoplastic Agents; Azepines; Drug Resistance, Neoplasm; Female; Humans; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Recurrence; Retreatment; Treatment Outcome

Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies.. Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25-90 mg for 14 or 21 consecutive days plus 14 or 7 days' rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/day once-daily (QD) for 14 days plus 14 days' rest, all in 28-day cycles. Subsequent cohorts received MLN8237 ECT 30-50 mg twice-daily (BID) for 7 days plus 14 days' rest in 21-day cycles.. Fifty-eight patients were enrolled (PIC n = 28, ECT n = 30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease.. The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Aurora Kinase A; Azepines; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines

Aberrant Myc expression plays a critical role in various tumors, including non-Hodgkin lymphoma (NHL). Myc-positive lymphoma is clinically aggressive, more resistant to chemotherapy, and associated with high mortality.. The current study aimed to show inhibition of aurora A kinase (AURKA) may overcome resistance to chemotherapy and improve outcomes in Myc-overexpressing lymphoma.. Myc-overexpressing lymphoma cell lines were evaluated by trypan blue, annexin V/propidium iodide staining, and western blotting for cytotoxicity, cell cycle, apoptosis, and Myc-associated protein expression, respectively, in the presence of cyclophosphamide with or without MLN8237, an AURKA inhibitor. Immunofluorescence for apoptosis-inducing factor (AIF) and acridine orange staining were used to analyze levels of autophagy. EµMyc genetically modified mouse model and xenograft models bearing Myc-overexpressing lymphoma cells were used to determine the efficacy of cyclophosphamide, MLN8237, or the combination in chemosensitive and chemoresistant tumors.. In our in vitro experiments using chemoresistant lymphoma cells, MLN8237 and cyclophosphamide showed synergistic effects. Mice bearing lymphoma xenograft had rapid disease progression with median survival of ~ 35 days when treated with cyclophosphamide alone. In contrast, the combination of cyclophosphamide and MLN8237 induced complete tumor regression in all mice, which led to improvement in survival compared with the single agent control (p = 0.022). Kinome analysis of tumors treated with MLN8237 showed global suppression of various kinases.. Our data demonstrate that AURKA inhibition induces synthetic lethality and overcomes chemoresistance in Myc-overexpressing lymphoma. The combination of MLN8237 and conventional chemotherapy showed promising safety and anti-tumor activities in preclinical models of Myc-positive NHL.

Topics: Animals; Antineoplastic Agents; Apoptosis; Aurora Kinase A; Azepines; Cell Cycle; Cell Line, Tumor; Cyclophosphamide; Drug Resistance, Neoplasm; Drug Synergism; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Lymphoma, Non-Hodgkin; Mice; Mice, Nude; Mice, Transgenic; Mutation; Proto-Oncogene Proteins c-myc; Pyrimidines

Aurora A and B are oncogenic serine/threonine kinases that regulate mitosis. Overexpression of Auroras promotes resistance to microtubule-targeted agents. We investigated mechanistic synergy by inhibiting the mitotic spindle apparatus in the presence of MLN8237 [M], an Aurora A inhibitor with either vincristine [MV] or docetaxel [MD] in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The addition of rituximab [R] to MV or MD was evaluated for synthetic lethality.. Aggressive B-NHL cell subtypes were evaluated in vitro and in vivo for target modulation and anti-NHL activity with single agents, doublets, and triplets by analyzing cell proliferation, apoptosis, tumor growth, survival, and mechanisms of response/relapse by gene expression profiling with protein validation.. MV is synergistic whereas MD is additive for cell proliferation inhibition in B-NHL cell culture models. Addition of rituximab to MV is superior to MD, but both significantly induce apoptosis compared with doublet therapy. Mouse xenograft models of mantle cell lymphoma showed modest single-agent activity for MLN8237, rituximab, docetaxel, and vincristine with tumor growth inhibition (TGI) of approximately 10% to 15%. Of the doublets, MV caused tumor regression, whereas TGI was observed with MD (approximately 55%-60%) and MR (approximately 25%-50%), respectively. Although MV caused tumor regression, mice relapsed 20 days after stopping therapy. In contrast, MVR was curative, whereas MDR led to TGI of approximately 85%. Proliferation cell nuclear antigen, Aurora B, cyclin B1, cyclin D1, and Bcl-2 proteins of harvested tumors confirmed response and resistance to therapy.. Addition of rituximab to MV is a novel therapeutic strategy for aggressive B-NHL and warrants clinical trial evaluation.

Topics: Animals; Antibodies, Monoclonal, Murine-Derived; Antigens, Nuclear; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Aurora Kinase A; Aurora Kinase B; Aurora Kinases; Azepines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin B1; Cyclin D1; Docetaxel; Gene Expression Profiling; Humans; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Mice; Mice, SCID; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Rituximab; Spindle Apparatus; Taxoids; Vincristine; Xenograft Model Antitumor Assays