Integrated preclinical and clinical development of S-trans, trans-Farnesylthiosalicylic Acid (FTS, Salirasib) in pancreatic cancer

Abstract

Purpose: S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA).

Patients and methods: In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naïve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients' biopsies were collected pre-treatment and on Cycle (C) 1, Day (D) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels. Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination.

Results: Salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. Salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes.

Conclusion: The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA.

Trial registration: ClinicalTrials.gov NCT00867230.

Conflict of interest statement

The terms of this arrangement were being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

Author’s Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following author (s) indicated a financial or other interest that is relevant to the subject matter under consideration in this manuscript. Those relationships marked with a “C” were compensated.

Employment or Leadership position: None

Consultant or Advisory Role: Rudek (C)

Stock Ownership: None

Research Funding: Laheru, Rudek

Expert Testimony: None

Other remuneration: None

Figures

Fig. 1

Efficacy and pharmacodynamic effect of salirasib on PDA PDX. PDX from PDA patients were implanted in athymic mice. Animals with established tumors were treated with the agents as mentioned in the materials and method section. a Anti-tumor effect of salirasib on the tumor growth of fourteen xenografts. Error bars represent standard error of mean (SEM); N=10 tumors per group (5 mice with bilateral flank tumors). Dotted line represents 50 % TGI. Salirasib treatment could reduce tumor volume by 50 % in 410 and 194 xenograft compared to vehicle treated animals. b Growth curves of A6L and 265 xenografts treated with vehicle, salirasib, GEM or combination of GEM and Salirasib. c Immunoblots showing that a combination of GEM and Salirasib treatment inhibits the expression of K-Ras, p-Akt, p-MEK (blots in side the green rectangle). C-PARP expression was up-regulated in the tumors of GEM or combination of GEM and salirasib treatment as compared to vehicle or salirasib treated tumors. Two separate tumors from the vehicle, salirasib, GEM and GEM plus salirasib treatment were homogenized. Lyates were resolved in SDS-PAGE and probed with specific antibodies against indicated proteins. β-actin was used as a loading control

Fig. 2

Average salirasib concentration-time profile. Average plasma concentration-time for all patients after salirasib was administered alone (day 7 or 22; A) or in combination with gemcitabine (day 15 or 8; B). The solid circle (Black Circle), open circle (○), solid triangle (Black Down-Pointing Triangle), and open triangle (White Triangle) represent 200 mg, 400 mg, 600 mg, and 800 mg, respectively. The error bars depict the standard deviation. Concentrations that were BLQ are represented as 0.5 ng/mL (i.e., 1/2 LOQ). Concentrations that were not trough samples were not utilized to calculate the average concentration for that time point

Fig. 3

Pharmacodynamic effects in paired tumor biopsies. a Data shown represent 24.75 % inhibition in total Ras and 43.65 % inhibition in KRas in Patient 019, a 67-year-old white male with metastases to the liver. b Data shown represent 16.09 % inhibition in total Ras and 42.81 % inhibition in KRas in Patient 023, a 55-year-old white female with metastases to the liver

Fig. 4

Waterfall plot of tumor measurement. Data are shown for patients with both baseline and post-baseline target lesion and CA19-9 measurements. Best response=maximum decrease from baseline in the sum of the longest diameters (SLD) of target lesions; if a decrease from baseline was not seen, the smallest increase from baseline in the SLD of target lesions is presented. [≥25 % increase from baseline in CA19-9 (blue); 25 % change from baseline in CA19-9 (yellow); and ≥25 % decrease from baseline in CA19-9 (red)]