A Phase II Study of AT-101 (Gossypol) in Chemotherapy-Sensitive Recurrent Extensive-Stage Small Cell Lung Cancer

Abstract

Background AT-101 is an oral inhibitor of the anti-apoptotic Bcl proteins (Bcl-2, Bcl-XL, Bcl-W, and Mcl-1) and an inducer of the pro-apoptotic proteins noxa and puma. We studied the efficacy of AT-101 in patients with recurrent chemosensitive extensive stage – small cell lung cancer (ES-SCLC). Methods Patients with recurrent “sensitive” SCLC (defined as no progression during and no disease recurrence < 2 months after completion of first-line platinum-based chemotherapy) were eligible. AT-101 was administered 20 mg orally daily for 21 out of 28 days each cycle for up to 6 cycles. The primary endpoint was the objective response rate. Results At the time of planned interim evaluation, none of the 14 evaluable patients enrolled in the first stage had any response to therapy and the study was closed permanently for further accrual. Three patients (21 %) achieved stable disease after two cycles of therapy. Grade 3 toxicities included anorexia, fatigue, and nausea/vomiting. Conclusions AT-101 is not active in patients with recurrent chemosensitive SCLC. Supported by N01-CM62205.

Gossypol sensitizes the antitumor activity of 5-FU through down-regulation of thymidylate synthase in human colon carcinoma cells

“…Gossypol can overcome gemcitabine resistance in cell lines with a high level of Bcl-2 expression and sensitize cancer cells to TRAIL or docetaxel in combination drug therapy [20][21][22]. Currently, gossypol is being evaluated in phase I and II clinical trials for use as a single agent or in combination with other anti-tumor agents in a variety of hematologic, lymphoid, and solid tumor malignancies [23,24]. However, the potential of gossypol to improve 5-FU sensitivity of colon cancer cells is unclear.…”

Origins, genetic landscape, and emerging therapies of small cell lung cancer

“…Even though inhibition of this protein showed promising effects in cell lines and xenografts, the clinical benefit of inhibition of BCL2 was limited. Antisense oligonucleotides and several compounds inhibiting BCL2 did not improve the outcome in SCLC patients (Rudin et al 2008;Baggstrom et al 2011;Langer et al 2014). However, a recent study brought new hope for the application of BCL2 inhibitors, as the combination of an mTOR inhibitor with a BCL2 inhibitor induced marked apoptosis in cell lines, xenografts, and GEMMs of SCLC (Faber et al 2015).…”

Targeting lactate metabolism for cancer therapeutics

“…Gossypol (also known as AT-101), a natural product found in cottonseed, is a nonselective inhibitor of LDH that blocks the binding of NADH, with a K i for LDHA and LDHB of 1.9 and 1.4 μM, respectively (50,51). This compound was initially developed as an antimalarial therapeutic, but is now being used in Phase I and Phase II clinical oncology trials (52)(53)(54). However, gossypol also inhibits GAPDH, which is an NAD + -dependent enzyme, and thus its antitumor activity may also include the inhibition of GAPDH.…”