Pharmacology
BCL-2 has been characterized in SCLC via immunohistochemistry, microarray
detection of mRNA, genomic sequencing and proteomic profiling with levels up
to 84%. In preclinical models, BCL-2 binds and sequesters BH3-only proapoptotic proteins BID or BIM and prevents them from interacting with the pore-forming effectors that lead to apoptosis and cell death. Understanding of the mechanism of BCL-2
proteins has led to two approaches to inhibiting this pathway, either by direct inhibition of BCL-2 or using BH-3 mimetics.
ABT-263, a BH3 mimetic, demonstrated antitumor activity in laboratory models
of SCLC but unfortunately has not led to repeated success in the clinic.
Phase II trials of ABT-263 have not demonstrated success. Out of 26 patients, only
1 showed a response to treatment with ABT-263.
Venetoclax, an effective BCL-2 inhibitor which has been effective clinically in
treating a variety of hematologic malignancies, has also been investigated.
Preclinical data appears promising as venetoclax, dosed at 100?mg/kg/qd, induced
tumor regression in mouse models, and further investigation is required.
