Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization. Protein phosphatase 2A (PP2A) is highly conserved and is the predominant serine/threonine phosphatase in the nervous system, constituting more than 70% of all neuronal phosphatases. PP2A is involved in diverse regulatory functions, including cell cycle progression, apoptosis, and DNA repair. Although PP2A has historically been identified as a tumor suppressor, inhibition of PP2A has paradoxically demonstrated potential as a therapeutic target for various cancers. LB100, a water-soluble, small-molecule competitive inhibitor of PP2A, has shown particular promise as a chemo- and radio-sensitizing agent. Preclinical success has led to a profusion of clinical trials on LB100 adjuvant therapies, including a phase I trial in extensive-stage small-cell lung cancer, a phase I/II trial in myelodysplastic syndrome, a phase II trial in recurrent glioblastoma, and a completed phase I trial assessing the safety of LB100 and docetaxel in various relapsed solid tumors. Herein, we review the development of LB100, the role of PP2A in cancer biology, and recent advances in targeting PP2A inhibition in immunotherapy.

4075 Background: Bevacizumab (B) + FOLFOX is widely accepted as a standard first-line therapy for metastatic colorectal cancer (mCRC). Recent treatment strategies have included the use of targeted therapies combined with chemotherapy to improve efficacy and to reduce chemotherapy-related toxicities. This Phase II study assesses first-line mFOLFOX6 + B + cetuximab (C), a monoclonal antibody approved for use in irinotecan-refractory mCRC. Methods: All pts had ECOG PS = 1, normal bone marrow, hepatic and renal function. Pts received mFOLFOX6 + B (5mg/kg) biweekly and C weekly (initially at 400 mg/m2, then subsequent doses at 250 mg/m2). Tumor assessment by imaging was done every 8 weeks. Primary endpoints are response rate, progression free-survival (PFS), overall survival (OS), and safety. The regimen would be considered promising if there were = 32 responses, or if = 60% of pts were progression-free for at least 8 months. Results: 67 pts (37 males, 30 females) were enrolled from 12/04–11/06. Median age was 57. Toxicities included Grade 4: neutropenia (6%), thrombosis/embolism (5%). Grade 3: neutropenia (13%), rash (13%), fatigue (11%), diarrhea (11%), abdominal pain (6%), neuropathy (5%), infection with ≤ Grade 2 ANC (4.5%). There were 2 deaths, 1 due to neutropenia and diarrhea and 1 to pulmonary fibrosis. As of 12/06, 9 pts were too early to evaluate. Of the remaining 58 pts, there were 32 responses (55%; 95% CI: 42%, 68%), including 3 CRs and 29 PRs; Median PFS was 9.6 months (95% CI: 8.8, 13.9 months), 71% were progression-free for at least 8 months, and median OS was not reached after a median follow-up of 11.4 months (range 1.5–25.2 months). Conclusions: Treatment with mFOLFOX6+ B + C met the pre-specified criteria for objective response and PFS to be considered promising. This regimen is associated with an acceptable toxicity profile and merits further evaluation. Supported by N01-CA-62204. No significant financial relationships to disclose.