iMYC: Proof-of-concept study of ibrutinib in c-MYC and HER2 amplified oesophagogastric carcinoma.

Abstract

TPS221 Background: The MYC proto-oncogene is among the most frequently dysregulated genes in human cancer and is amplified in 10-30% of oesophagogastric (OG) cancers. Such genes which code for transcription factors are challenging to target directly with small molecule inhibitors or monoclonal antibodies. High-throughput siRNA screening of OG cell lines has found silencing of Bruton’s tyrosine kinase (BTK) to result in selective lethality in the presence of MYC amplification. Sensitivity to the orally available BTK inhibitor ibrutinib has been confirmed in-vitro in MYC, HER2 and co-amplified OG cancer cell lines (Chong, Ann Onc 2014), suggesting it may be a potentially effective therapeutic strategy in both MYC and HER2 amplified OG cancer. Methods: i MYC is an open label, phase II non-randomised study to assess the efficacy of ibrutinib in advanced pre-treated OG cancer. A novel FISH assay for tumour MYC amplification has been developed and pts are pre-screened for MYC and HER2 amplification. Eligibility includes metastatic or locally advanced inoperable OG cancer (SCC or adeno), MYC (ratio >2.5) and/or HER2 (ratio>2) amplification, progression after at least 1 prior line of chemotherapy +/- trastuzumab for advanced disease, PS 0-2 and no history of significant cardiovascular or bleeding disorders. Of the first 9 pts, at least 4 will demonstrate MYC amplification and remaining 5 will show either MYC or HER2 amplification, or co-amplification of both. Pts will be treated with ibrutinib monotherapy until progression or unacceptable toxicity. A Simon 2 stage design will be used for the primary endpoint of response rate, with interim analysis after 9 pts and maximum recruitment to 17 pts. Secondary endpoints include PFS, OS and exploratory translational and imaging biomarker analysis. Mandatory biopsy will be obtained at baseline and optional biopsies will be undertaken at day 10-14, week 8 and progression. The trial represents the first attempt at targeting MYC amplification via synthetic lethal gene interactions in OG cancer through the novel application of an existing anti-cancer drug. As of September 2016, 61 patients have consented for pre-screening, 19 completed MYC analysis and first patient has started treatment. Clinical trial information: 02884453.

BTK inhibition sensitizes acute lymphoblastic leukemia to asparaginase by suppressing the amino acid response pathway

“…28,29 Whereas overexpression of c-Myc enhances BCR signaling, 30 inhibition of c-Myc can be used to prevent or overcome ibrutinib resistance. 31 The notion that ibrutinib suppresses c-Myc function in solid tumors 32,33 has led to the development of clinical trials studying the efficacy of ibrutinib in Myc-transformed tumors. To confirm a role for c-Myc in the suppression of the GCN2-ATF4 pathway in response to ibrutinib, we investigated whether loss of c-Myc activity would mirror the effects of ibrutinib on ASNase-induced apoptosis.…”