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Published on: September 8, 2017
Farnesyl transferase expression determines clinical response to the docetaxel-lonafarnib combination in patients with
John Kauh1, Chantal Chanel-Vos, Daniel Escuin
1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, USA.
Background:
Lonafarnib (LNF) is a protein farnesyl transferase (FTase) inhibitor that has shown synergistic activity with taxanes in preclinical models and early stage clinical trials. Preclinical findings suggested tubulin acetylation and FTase expression levels may be important determinants of drug sensitivity that would help identify patient populations more likely to benefit from this regimen. This pilot study evaluated the biological effects of LNF and docetaxel (DTX) combination therapy in refractory solid tumors by comparing pretreatment and post-treatment tumor biopsies.
Methods:
Patients with histologically confirmed locally advanced or metastatic solid malignancies refractory to standard therapies or with no effective therapies available were eligible. Patients were randomized to 1 of 4 dosing cohorts: 1) 30 mg/m², 100 mg; 2) 36 mg/m², 100 mg; 3) 30 mg/m², 150 mg; or 4) 36 mg/m², 150 mg of DTX intravenously weekly, LNF orally twice daily, respectively.
Results:
Of the 38 patients enrolled, 36 were treated, and 29 were evaluable for toxicity and response assessment. The combination of LNF and DTX was tolerated in all cohorts with the exception of a 28% incidence of grade 3/4 diarrhea, which was manageable with aggressive antidiarrheal regimens. Seven patients derived clinically meaningful benefit from this combination treatment; these patients had significantly lower basal FTase-beta mRNA expression levels than the mean study population level (P < .05). Correlation of clinical benefit with tubulin acetylation content as well as basal acetyl-tubulin content were evaluated. However, no significant correlation was found.
Conclusions:
Despite the small number of patients, these findings support our preclinical mechanistic studies and warrant further clinical investigations using FTase-beta mRNA expression as a potential predictive biomarker to select for an enriched patient population to study the effects of taxane and FTase inhibitor combination therapies.
Insights
This study investigated lonafarnib and docetaxel combination therapy in solid tumors. Lower FTase-beta mRNA levels predicted patient benefit, suggesting its use as a biomarker for this cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Lonafarnib (LNF), a farnesyl transferase inhibitor, shows synergy with taxanes.
- Preclinical data suggest tubulin acetylation and FTase levels predict sensitivity to LNF and taxane combinations.
- This pilot study assessed biological effects of LNF and docetaxel (DTX) in refractory solid tumors.
Purpose of the Study:
- To evaluate the biological effects of LNF and DTX combination therapy.
- To identify potential predictive biomarkers for patient selection in future clinical trials.
Main Methods:
- Pilot study involving patients with refractory solid tumors.
- Randomized dosing cohorts of LNF and DTX.
- Comparison of pre- and post-treatment tumor biopsies.
Main Results:
- Combination therapy was generally tolerated, with manageable grade 3/4 diarrhea.
- Seven patients showed clinical benefit, correlating with significantly lower basal FTase-beta mRNA expression.
- No significant correlation was found between clinical benefit and tubulin acetylation levels.
Conclusions:
- FTase-beta mRNA expression may serve as a predictive biomarker for LNF and taxane combination therapy.
- Further clinical investigation is warranted to validate FTase-beta mRNA as a predictive biomarker.
- Findings support preclinical data on the role of FTase in drug sensitivity.
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