Abstract
Background: TRC102 inhibits base excision repair by binding abasic sites and preventing AP endonuclease processing; it potentiates the activity of alkylating agents, including temozolomide, in murine models. In published xenograft studies, TRC102 enhanced the antitumor effect of temozolomide regardless of cell line genetic characteristics, e.g., O6-methylguanine DNA methyltransferase (MGMT), mismatch repair (MMR), or p53 status.Materials and Methods: We conducted a phase 1 trial of TRC102 with temozolomide given orally on days 1-5 of 28-day cycles in adult patients with refractory solid tumors that had progressed on standard therapy. Tumor induction of nuclear biomarkers of DNA damage response (DDR) γH2AX, pNBs1, and Rad51 was assessed in the context of MGMT and MMR protein expression for expansion cohort patients.Results: Fifty-two patients were enrolled (37 escalation, 15 expansion) with 51 evaluable for response. The recommended phase 2 dose was 125 mg TRC102, 150 mg/m2 temozolomide QDx5. Common adverse events (grade 3/4) included anemia (19%), lymphopenia (12%), and neutropenia (10%). Four patients achieved partial responses (1 non-small cell lung cancer, 2 granulosa cell ovarian cancer, and 1 colon cancer) and 13 patients had a best response of stable disease. Retrospective analysis of 15 expansion cohort patients did not demonstrate a correlation between low tumor MGMT expression and patient response, but treatment induced nuclear Rad51 responses in 6 of 12 patients.Conclusions: The combination of TRC 102 with temozolomide is active, with 4 of 51 patients experiencing a partial response and 13 of 51 experiencing stable disease, and the side effect profile is manageable.
Highlights
Among the various mechanisms by which resistance to chemotherapy can develop, aberrations in the base excision repair (BER) pathway have been reported to play a major role in promoting resistance to alkylating and antimetabolite chemotherapy [1]
Four patients achieved partial responses (1 non-small cell lung cancer, 2 granulosa cell ovarian cancer, and 1 colon www.oncotarget.com cancer) and 13 patients had a best response of stable disease
Retrospective analysis of 15 expansion cohort patients did not demonstrate a correlation between low tumor methylguanine DNA methyltransferase (MGMT) expression and patient response, but treatment induced nuclear Rad51 responses in 6 of 12 patients
Summary
Among the various mechanisms by which resistance to chemotherapy can develop, aberrations in the BER pathway have been reported to play a major role in promoting resistance to alkylating and antimetabolite chemotherapy [1]. TMZ alkylates guanine at the O6 position, producing the well-known O6-methylguanine (O6-MG) lesion, which incorrectly base pairs with thymine [7] Recognition of this error by the MGMT enzyme allows for the direct removal of the methyl/alkyl group from the O6 position by the same protein and restores guanine to its normal form, making MGMT critical to single-agent TMZ resistance [8]. The combination of low tumor MGMT expression and a functional MMR pathway is often considered necessary for TMZ activity, tumor characteristics that only a subset of patients demonstrate. TRC102 inhibits base excision repair by binding abasic sites and preventing AP endonuclease processing; it potentiates the activity of alkylating agents, including temozolomide, in murine models. TRC102 enhanced the antitumor effect of temozolomide regardless of cell line genetic characteristics, e.g., O6-methylguanine DNA methyltransferase (MGMT), mismatch repair (MMR), or p53 status
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