Obatoclax mesylate is an intravenously-administered
drug under investigation in Phase I and II clinical trials as a novel anticancer therapeutic for
hematological malignancies and solid
tumors.
Obatoclax was developed as a pan-inhibitor of antiapoptotic members of the
B cell chronic lymphocytic leukemia/
lymphoma 2 (BCL-2) family of
proteins, which control the intrinsic or mitochondrial pathway of apoptosis. Resistance to apoptosis through dysregulation of BCL-2 family members is commonly observed in
hematological malignancies, and can be linked to therapeutic resistance and poor clinical outcomes. By inhibiting pro-survival BCL-2 family
proteins, including MCL-1,
obatoclax is proposed to (1) trigger cell death as a single agent, and (2) potentiate the anticancer effects of other
therapeutics. Preclinical investigations have supported these proposals and have provided evidence suggestive of a promising therapeutic index for this
drug. Phase I trials of
obatoclax mesylate in
leukemia and
lymphoma have defined well-tolerated regimens and have identified transient neurotoxicity as the most common adverse effect of this
drug. In these studies, a limited number of objective responses were observed, along with hematological improvement in a larger proportion of treated patients. Published Phase II evaluations in
lymphoma and
myelofibrosis, however, have not reported robust single-agent activity. Emerging evidence from ongoing preclinical and clinical investigations suggests that the full potential of
obatoclax mesylate as a novel
anticancer agent may be realized (1) in rational combination treatments, and (2) when guided by molecular predictors of therapeutic response. By understanding the molecular underpinnings of
obatoclax response, along with optimal therapeutic regimens and indications, the potential of
obatoclax mesylate for the treatment of
hematological malignancies may be further clarified.