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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

Medullary thyroid carcinoma (MTC), a neuro-endocrine cancer of parafollicular C-cells accounts for 4-10% of all thyroid cancers and has low response rates to “cytotoxic chemotherapy”. The RET proto-oncogene encodes the RET (Rearranged during Transfection) transmembrane tyrosine kinase (TK) receptor, a pivotal player and a logical target for treatment of MTC. While trials with vandetanib (V) a RET TK inhibitor (TKI) in patients with MTC have been promising, we recognized a TKI is unlikely to have maximum benefit administered alone. We sought to combine V + a drug with a broad activity profile and no overlapping toxicities. Recognizing the failure of traditional “cytotoxic” agents we investigated the proteasome (Pr) inhibitor, bortezomib (B) not yet explored clinically in MTC. Initial experiments using TT MTC cells with a mutant C634W RET, found V + B non-antagonistic in cytotoxicity assays, and V showed decreased phospho-RET expression in TT cells with 0.5 or 1 µM in 1.5h. But while V did not change RET protein levels, B decreased RET protein 7 fold and secondarily phospho-RET levels. That this was secondary to Pr inhibition and not unique to B was confirmed by treating TT cells 6h or 24h with three other Pr inhibitors – epoxomycin, lactacystin or MG132. We observed 5-9 fold decreases in RET protein, which followed a time course and a dose response, with greater reduction at 24h than at 6h. To assess if the decrease in RET protein was due to decreased RET mRNA levels, we assessed RET mRNA expression and were surprised to find a 4-9 fold decrease with Pr inhibitors. Since Pr inhibitors reduced RET by reducing mRNA levels, and reasoning this would provide an alternate strategy to impact RET function, we studied the effect of three HDAC inhibitors on RET mRNA and protein expression. Treatment of TT cells with vorinostat, belinostat, or romidepsin (R) decreased RET mRNA 3-4 fold at 24h and protein levels 4 and 7-14 fold, at 24 and 48h respectively. Furthermore B + R had greater impact than either drug separately, depressing RET protein in TT cells an additional 2-3 fold to levels 4-12 fold less than that in untreated cells, suggesting mechanisms whereby Pr and HDAC inhibitors reduce mRNA levels might differ. We have pursued the latter by examining mRNA and protein levels of 3 candidate transcription factors identified in a literature search. To date we have shown TTF1 and E2F1 mRNA levels are decreased 4-58 fold by both Pr and HDAC inhibitors whereas EGR1 levels only fall with Pr inhibitors. siRNA studies that modulate transcription factor levels will clarify their possible roles in the Pr and HDAC inhibitor drug effects and help elucidate whether these inhibitors, either alone or in combination, can prove useful in MTC therapy by reducing the crucial RET TK. 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 4547. doi:10.1158/1538-7445.AM2011-4547