Wadsworth, J. Trad

Abstract Background: Stage IVC (metastatic) anaplastic thyroid cancer (ATC) has a median overall survival (OS) of only 1.9 months. Single agent paclitaxel has modest activity in ATC. In pre-clinical studies, CS-7017 inhibited ATC proliferation through a novel mechanism–activation of PPAR-γ, followed by sequential upregulation of RhoB, then p21. Moreover, CS-7017 augmented the proapoptotic effects of paclitaxel. Based on these results, a multicenter study was conducted to determine if CS-7017+paclitaxel might prove safe and effective in advanced ATC. Design: A Phase 1 study was conducted to determine the Phase 2 dose. In Phase 1, patients received CS-7017 orally BID for one week (run-in phase), followed by a 3 h iv infusion of paclitaxel (175 mg/m2) every 3 weeks in combination with BID CS-7017. CS-7017 doses were escalated (0.15, 0.3, or 0.5 mg). Tissue biopsies were obtained at baseline and at one and three weeks for immunohistochemistry of PPAR-γ responsive proteins; serum CS-7017 PK studies were also performed. Results: Nineteen patients were enrolled, but 4 were not dosed (3 due to progression, 1 ineligible). Seven participated in CS-7017 dose levels 1a/1b (0.15 mg BID), six in dose level 2 (0.3 mg BID), and two in dose level 3 (run-in phase only–0.5 mg BID). Demographics: Of the 15 treated patients, 10 (67%) were women. Median age was 59 years (range: 43-82) Efficacy: Of 15 patients receiving drug, one had a confirmed partial response (PR) lasting from Day 69 to Day 175, and eight had stable disease (SD) as their best response. Median Time to Progression in 7 patients at Dose Level 1 was 49 days, but 70 days in Dose Level 2 (43% prolongation); corresponding median survival was 99 (0.15 mg BID) vs. 140 days (0.3 mg BID, 42% increase). Median peak CS-7017 blood level was 8.6 ng/mL (range: 5.1 to 13.7) for Level 1 and 22.0 ng/mL (17.0 to 31.5) for Dose Level 2. Adverse Events: Ten patients had AEs ≥ Grade 3, with two (anemia and localized edema) related to CS-7017. Thirteen events of fluid retention/edema were reported in 8 patients, with only 2 events of CTCAE grade ≥ 3. Eight patients had ≥ one SAE, with one (anemia) due to CS-7017. One SAE (anaphylactic reaction) was related to paclitaxel. No dose limiting toxicity was observed. Immunohistochemistry: Biopsies were available on 7 patients. PPAR-γ, RXR-α, RhoB were present in all; Angiopoietin-like 4 was induced by CS-7017. Conclusions: Combination therapy with CS-7017 and paclitaxel was tolerated and has biologic activity in patients with metastatic anaplastic thyroid carcinoma, with initial exploratory data suggesting a dose-dependent improvement in time to progression and survival in response to escalating CS-7017 dosage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1278. doi:10.1158/1538-7445.AM2011-1278

Abstract Anaplastic thyroid carcinoma (ATC) is a highly aggressive form of the disease for which new therapeutic options are desperately needed. Previously, we showed that the high-affinity peroxisome proliferator–activated receptor γ (PPARγ) agonist, RS5444, inhibits cell proliferation of ATC cells via induction of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21). We show here that up-regulation of RhoB is a critical step in PPARγ-mediated activation of p21-induced cell stasis. Using multiple independently derived ATC cell lines, we found that treatment with RS5444 leads to the up-regulation of RhoB and subsequent activation of p21, and that silencing of RhoB by RNAi blocks the ability of RS5444 to induce p21 and to inhibit cell proliferation. Our results show that transcriptional regulation of RhoB by the nuclear transcription factor PPARγ is responsible for the induction of p21 mRNA and protein. We further implicate RhoB as a key signaling effector for the growth inhibition of ATC, as treatment with a histone deacetylase inhibitor shown to increase RhoB expression in lung cancer cells caused the up-regulation of RhoB in ATC cells accompanied by increased expression of p21 and inhibition of cell proliferation; this effect occurred even in ATC cells that were unresponsive to RS5444 due to a lack of expression of PPARγ. Our results implicate RhoB as a novel intermediate in critical signaling pathways and as an additional target for therapeutic intervention in ATC. [Cancer Res 2009;69(4):1536–44]