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H. Paripati
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-074 - Phase I-II Trial of Combined PKC Iota and mTOR Inhibition for Patients with Advanced or Recurrent Lung Cancer - A Trial in Progress (ID 2823)
09:30 - 09:30 | Author(s): H. Paripati
- Abstract
Background:
Cancer stem cells may be responsible for initiation, maintenance, progression and metastatic spread of lung cancers and native or acquired drug resistance can allow cancers to escape from conventional therapy. Eradicating cancer stem cells may improve clinical outcomes. We (APF, VJ) showed that PKCi is an oncogene for NSCLC and is amplified in most squamous lung cancer cells (LSCC). PKCι is required for LSCC cell proliferation in vitro and tumorigenicity in vivo and for maintenance of the lung cancer tumor initiating cell (TIC) phenotype. LSCC oncospheres have cancer stem cell characteristics, express stem genes, and exhibit clonal expansion, enhanced transformed growth and the ability to maintain lung tumors and metastases in vivo. The PKCi-Rac1-Ect2-MMP10 signaling axis is activated in LSCC TICs and PKCι knock down, impairs soft agar growth, clonal expansion and tumorigenicity. The gold salt auranofin (ANF) reproduces the effects of PKCι knock down on the PKCi-Rac1-Ect2-MMP10 signaling pathway and on clonal expansion and tumorigenicity. ANF potently and selectively inhibits oncogenic PKCι signaling and combined PKCι and mTOR inhibition synergistically reduces lung cancer cell proliferation and tumor growth in vivo and in vitro (Ross H, Justilien V, Hill K, Walsh M, Fields AP. Protein kinase C iota is required for maintenance of a tumor initiating cell phenotype in lung squamous cell carcinoma. Abstract 2644 WCLC 2013). A phase I/II clinical trial of oral ANF + the mTOR inhibitor sirolimus in patients with advanced or recurrent lung cancer is ongoing.
Methods:
A phase I/II clinical trial is accruing patients to test the hypothesis that combined inhibition of PKCι and mTOR is safe and effective in lung cancer patients. NCT01737502 NCI sponsored clinical trial R21 CA153000 Eligible participants are adults with confirmed diagnosis of lung cancer (squamous, RAS-mutated adenocarcinoma or small cell lung cancer), PS 0-2, adequate organ function, no significant comorbidities and who have completed at least one prior course of platinum doublet chemotherapy. Patients receive ANF + sirolimus orally daily in 28 day continuous cycles. Tumor biopsies are collected for biomarker assessment focused on the PKCi-Rac1-Ect2-MMP10 pathway. Study endpoints are safety, survival and biomarker development.
Results:
The trial has completed the phase I portion with six patients without dose limiting toxicity. The phase II portion of the trial is now accruing with doses of ANF 6 mg daily and sirolimus 5 mg daily continuously in 28 day cycles. Biomarker assessment is ongoing.
Conclusion:
The phase I portion of this trial demonstrated preliminary safety of the combination of auranofin and sirolimus at doses that were effective against NSCLC in preclinical models. Phase II accrual is ongoing.
