David J. Park

Thymidylate synthase gene polymorphism predicts response to capecitabine in advanced colorectal cancer

Abstract. Thymidylate synthase is a target enzyme for chemotherapeutic agents such as 5-fluorouracil and capecitabine, its oral prodrug. The human thymidylate synthase gene promoter is polymorphic, having either double or triple repeats of a 28-bp sequence. It has previously been shown that colorectal cancer patients who are homozygous for the triple tandem repeats (L/L) have significantly higher thymidylate synthase mRNA expression than those homozygous for the double repeat variant (S/S). Capecitabine is converted to 5-fluorouracil by a sequential triple enzyme pathway, with the last step catalyzed by the tumor-associated angiogenic factor thymidine phosphorylase. We have recently shown that individuals with metastatic colorectal cancer treated with 5-fluorouracil have a higher response rate if they are homozygous for the genotype S/S as opposed to S/L or L/L. Our hypothesis is that individuals homozygous for the double repeat variant (S/S) should have a better response to capecitabine than their counterparts with S/L or L/L. In this retrospective pilot study we assessed the thymidylate synthase polymorphic status of 24 patients with metastatic colorectal cancer and determined their response to capecitabine. We found that 75% (3/4) of individuals with the S/S variant responded to capecitabine, compared to 8% (1/12) and 25% (2/8) of those with the S/L and L/L variants, respectively. Our data suggest that genotyping patients for the thymidylate synthase polymorphism would be useful in identifying patients who are more likely to respond to capecitabine treatment for advanced colorectal cancer.

Tailoring chemotherapy in advanced colorectal cancer

In this post-genomic era, the individualization of chemotherapy through the study of pharmacogenetics is becoming an ever attainable reality. Keys to individual variations in drug response and toxicity are being identified through the study of drug targets, metabolizing enzymes, efflux and DNA repair systems at the genomic, mRNA and protein levels. Several promising pharmacogenetic candidates with predictive and/or prognostic value have been identified. These candidates, along with others yet to be identified, could in the near future allow for the tailoring of therapy with an ever increasing chemotherapeutic armamentarium. Well-designed and large prospective analyses, which include relevant pharmacogenetic parameters, are needed to confirm the initial clinical associations reported thus far.

The role of proteasome inhibitors in solid tumors.

The proteasome is a multicatalytic protein complex whose principal task is the degradation of a large array of proteins within the cell. Its substrates include proteins involved in cell cycle regulation, tumor suppression, apoptosis, transcription, and angiogenesis, among others. This makes the inhibition of the proteasome a promising novel therapeutic approach to cancer treatment. Bortezomib (Velcade) is the first proteasome inhibitor to have shown anti‐cancer activity and reached clinical trials. Preclinical and early clinical trials in both solid tumors and hematological malignancies demonstrate that bortezomib is a relatively well‐tolerated and active agent, either alone or in combination with traditional chemotherapeutic drugs. Clinical trials that may help delineate the role of bortezomib in the treatment solid tumors either as single agent or in combination are ongoing.

Abstract 4664: Result of TORI L-03, a randomized, multicenter phase II clinical trial of erlotinib (E) or E + fulvestrant (F) in previously treated advanced non-small cell lung cancer (NSCLC).

Background: EGFR inhibition is an established therapy for previously treated NSCLC. Estrogen receptors (ER) and aromatase are expressed in most NSCLC specimens in both men and women. In preclinical models, estrogen stimulates NSCLC growth, an effect blocked by F, a pure ER antagonist. Preclinical models show enhanced anti-tumor effects by combining EGFR inhibitors with F. Methods: We conducted a Phase II clinical study to evaluate whether addition of F enhances antitumor efficacy of E. Men and women with advanced NSCLC and > 1 prior chemotherapy regimen (unless patient refused) were randomized 2:1 to receive E (150 mg PO qd) + F (500 mg IM q2wk x 3, then q4wk) or E alone. Stratification for gender and ECOG (0, 1 vs. 2) was performed. Response rate (RR) was the primary endpoint. Secondary endpoints included progression free survival (PFS), overall survival (OS) and correlation between clinical endpoints and tumor tissue and blood-based biomarkers. Results: 106 patients (pts) were randomized from March 2006 to June 2010. 100 (evaluated population) received E +/- F. E + F was well tolerated, with adverse events well balanced between arms. For E + F and E respectively, RR (23.6% vs. 14.8%, p = 0.35), PFS [1.9 vs. 1.8 months, hazard ratio (HR) 0.85, 95% confidence interval 0.55, 1.33] and OS [9.4 vs. 5.7 months, HR 0.96 (0.6, 1.55)] were similar between arms. EGFR mutational data could be obtained on 69 pts. EGFR mutations were more prevalent in the E arm (35% vs. 20%). EGFR mutations strongly predicted best response, PFS and OS (p Conclusion: E + F was well tolerated in previously treated NSCLC pts, including men and pre- and post-menopausal women. The study showed a high RR (23.6%) for E + F, that was not adequately explained by EGFR mutations. Among EGFR WT pts, a significantly higher CBR that included 3 PRs was seen with trends towards improved PFS and OS with E + F as compared to E alone. Evaluation of tumor tissue biomarkers (including ER-α and -β, aromatase), blood estrogen levels and EGFR ligands known to be induced by ER signaling is ongoing to determine NSCLC subpopulations most likely to benefit from antiestrogens. [Supported by 1K23CA149079, P50 CA090440, V Foundation for Cancer Research, Jonsson Comprehensive Cancer Center, Wolfen Family Lung Cancer Research Program, Stiles Program in Oncology, National Lung Cancer Partnership and One Ball Matt Memorial Golf Tournament] Citation Format: Edward B. Garon, Jill M. Siegfried, Steven M. Dubinett, Robert M. Elashoff, David J. Park, Rupesh J. Parikh, Ravi Patel, Eddie H. Hu, Karen L. Reckamp, Brad Adams, Diego Martinez, He-Jing Wang, Fairooz Kabbinavar, Sanja Dacic, Meghan Brennan, Isett Laux, Diana C. Marquez-Garban, Laura P. Stabile, Dennis J. Slamon, Richard J. Pietras. Result of TORI L-03, a randomized, multicenter phase II clinical trial of erlotinib (E) or E + fulvestrant (F) in previously treated advanced non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4664. doi:10.1158/1538-7445.AM2013-4664

Proteasome Inhibition and Its Clinical Application in Solid Tumors

The proteasome is a multicatalytic protein complex whose principal function is the degradation of vital proteins many of which are involved in cell cycle regulation, tumor suppression, apoptosis, transcription, and angiogenesis. The inhibition of the proteasome is a promising novel therapeutic approach to cancer treatment. Bortezomib (Velcade) is the first proteasome inhibitor to have shown anticancer activity and reach clinical trials. Preclinical and early clinical trials in both solid tumors and hematological malignancies demonstrate that bortezomib is a relatively well-tolerated and active agent, either alone or in combination with traditional chemotherapeutic drugs. Most recently, its efficacy has been shown in multiple myeloma. Currently, clinical trials are ongoing in order to determine the efficacy as well as safety of bortezomib in the management of solid tumors, especially in combination with traditional cytotoxic agents.