Gordon M.S.,Pinnacle Oncology Hematology |
Rosen L.S.,University of California at Los Angeles |
Mendelson D.,Pinnacle Oncology Hematology |
Ramanathan R.K.,Virginia per Cancer Center Clinical Trials At Scottsdale Healthcare Vgpcc |
And 14 more authors.
Investigational New Drugs | Year: 2013
Introduction TRC102 potentiates the activity of cancer therapies that induce base excision repair (BER) including antimetabolite and alkylating agents. TRC102 rapidly and covalently binds to apurinic/apyrimidinic (AP) sites generated during BER, and TRC102-bound DNA causes topoisomerase II-dependent irreversible strand breaks and apoptosis. This study assessed the safety, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of TRC102 alone and in combination with pemetrexed. Purpose Patients with advanced solid tumors received oral TRC102 daily for 4 days. Two weeks later, patients began standard-dose pemetrexed on day 1 in combination with oral TRC102 on days 1 to 4. The pemetrexed-TRC102 combination was repeated every 3 weeks until disease progression. Methods Twenty-eight patients were treated with TRC102 at 15, 30, 60 or 100 mg/m2/d. The MTD was exceeded at 100 mg/m2/d due to grade 3 anemia in 50 % of patients. TRC102 exposure increased in proportion to dose with a mean t1/2 of 28 h. A pharmacodynamic assay confirmed that TRC102 binds to pemetrexed-induced AP sites at all doses studied. Stable disease or better was achieved in 15 of 25 patients evaluable for response (60 %), including one patient with recurrent metastatic oropharyngeal carcinoma that expressed high levels of thymidylate synthase, who achieved a partial response and was progression free for 14 months. Conclusions When administered with pemetrexed, the maximum tolerated dose of oral TRC102 is 60 mg/m2/d for 4 days. Randomized controlled studies are planned to evaluate the clinical benefit of adding TRC102 to pemetrexed and other agents that induce BER. © 2012 Springer Science+Business Media, LLC.
Weiss G.J.,Virginia per Cancer Center Clinical Trials At Scottsdale Healthcare Vgpcc |
Weiss G.J.,The Translational Genomics Research Institute |
Liang W.S.,The Translational Genomics Research Institute |
Izatt T.,The Translational Genomics Research Institute |
And 15 more authors.
PLoS ONE | Year: 2012
Background: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal tract with little molecular characterization. We performed whole genome sequencing (WGS) on paired normal and tumor DNA from a patient with metastatic-ONB to identify the somatic alterations that might be drivers of tumorigenesis and/or metastatic progression. Methodology/Principal Findings: Genomic DNA was isolated from fresh frozen tissue from a metastatic lesion and whole blood, followed by WGS at >30X depth, alignment and mapping, and mutation analyses. Sanger sequencing was used to confirm selected mutations. Sixty-two somatic short nucleotide variants (SNVs) and five deletions were identified inside coding regions, each causing a non-synonymous DNA sequence change. We selected seven SNVs and validated them by Sanger sequencing. In the metastatic ONB samples collected several months prior to WGS, all seven mutations were present. However, in the original surgical resection specimen (prior to evidence of metastatic disease), mutations in KDR, MYC, SIN3B, and NLRC4 genes were not present, suggesting that these were acquired with disease progression and/or as a result of post-treatment effects. Conclusions/Significance: This work provides insight into the evolution of ONB cancer cells and provides a window into the more complex factors, including tumor clonality and multiple driver mutations. © 2012 Weiss et al.