In preclinical testing, Mount Sinai School of Medicine researchers demonstrated the anti-ovarian cancer effectiveness of AT-406, an inhibitor of apoptosis proteins, as a single agent and in the combination with carboplatin. As of this writing, Ascenta Therapeutics is conducting an open and ongoing phase I clinical study in patients with advanced solid tumors and lymphomas.
Apoptosis Proteins: A Promising Target For Cancer Therapeutics?
Apoptosis increasing from normal cells (top) to apoptotic ones (bottom). (Photo: Wikipedia)
Human cells are programmed to survive, die or proliferate through a complex system of regulatory controls. Apoptosis — also know as “programmed cell death” — is a precisely regulated, complex process through which normal cells in the body die after a given life span, ensuring that defective, damaged, or redundant cells are eliminated.
The human body use apoptosis, or programmed cell death, to eliminate abnormal or unwanted cells. As a result of accumulated genomic alterations, it seems that cancer cells often fail to execute an apoptotic program, which allows them to live indefinitely and grow uncontrollably. The breakdown of the cellular apoptosis regulatory machinery is sometimes a dominant characteristic of cancer. Many current cancer therapies, including chemotherapeutic agents, radiation, and immunotherapy, work by inducing apoptosis in cancer cells. However, because the normal apoptotic biological pathways are sometimes defective, many cancer cells are inherently resistant or develop resistance to various therapies. An emerging direction for drug development involves the direct targeting of apoptotic proteins to induce cell death and/or reduce treatment resistance.
AT-406 — A New Inhibitor of Apoptosis Proteins — is Effective in Preclinical Testing Against Ovarian Cancer.
(Photo: University of Michigan Heath System)
AT-406 is a novel and orally-active small molecule drug designed to promote programmed cell death (apoptosis) in tumor cells by blocking the activity of inhibitors of apoptosis proteins (IAPs), including XIAP, c-IAP1, c-IAP2, and ML-IAP, to create conditions in which apoptosis can proceed. Based on this designed activity, AT-406 is best described as a multi-IAP inhibitor. IAPs are key components of the complex cascade of protein signaling that activates enzymes (called “caspases“) to initiate the breakdown of the cancer cell. AT-406 is thought to mimic the activity of Smac (second mitochondria-derived activator of caspases) by binding to XIAP and preventing it from inhibiting caspase activation. Upon binding to cIAP1 and cIAP2, AT-406 induces rapid degradation of these proteins and promotes apoptosis through activation of the death-receptor complex and caspase 8.
Ascenta Therapeutics (Ascenta), the developer of AT-406, reported that the drug has already demonstrated single-agent antitumor activity in multiple preclinical xenograft models of human cancer, including breast cancer, pancreatic cancer, prostate cancer, and lung cancer. Ascenta also noted that AT-406 has also been shown to work synergistically with conventional chemotherapeutic and targeted agents (such as TRAIL and tyrosine kinase inhibitors) in preclinical tumor models.
Mount Sinai School of Medicine researchers evaluated AT-406 in ovarian cancer cells as a single agent, and in the combination with carboplatin, for therapeutic effectiveness and mechanism of action. The researchers reported that AT-406 had significant single agent activity in 60% of the human ovarian cancer cell lines examined in vitro, and inhibited ovarian cancer progression in vivo. Notably, three of the five carboplatin-resistant cell lines tested sensitive to AT-406, thereby highlighting the therapeutic potential of AT-406 for patients with inherent or acquired platinum drug resistance.
Additionally, the researchers also determined that AT-406 enhanced carboplatin-induced ovarian cancer cell death and increased the survival of the experimental in vivo test mice. This result suggests a synergy created by this two drug combination, whereby AT-406 sensitizes the response of these cancer cells to carboplatin. From a mechanism of action perspective, the researchers demonstrated that AT-406 induced apoptosis correlated with the drug’s ability to down-regulate XIAP, whereby AT-406 induces cIAP1 degradation in both AT-406 sensitive and resistant cell lines. Collectively, these results demonstrate, for the first time, the anti-ovarian cancer efficacy of AT-406 as a single agent and in the combination with carboplatin. The researchers believe that AT-406 may represent a novel therapy for ovarian cancer patients, especially for patients exhibiting resistance to the platinum-based therapies.
Initial Phase I Clinical Study of AT-406 in Patients With Advanced Solid Tumors & Lymphomas
Ascenta is currently conducting clinical trials of AT-406 within the U.S. in patients with a variety of solid tumors and lymphomas. As of this writing, Ascenta is conducting a phase I, dose-escalation, open-label, multi-center study (University of Michigan Comprehensive Cancer Center, Mayo Clinic, and Duke University Medical Center) in patients with advanced solid tumors and lymphomas to evaluate the safety, tolerability and pharmacology of AT-406 when administered orally. The ClinicalTrials.gov Identifier Number for this trial is NCT01078649.
It is important to note that phase I trials usually enroll a small numbers of patients who have advanced cancer that cannot be treated effectively with standard treatments, or for which no standard treatment exists. Although evaluating the effectiveness of a drug is the primary goal of a phase II (not phase I) clinical study, medical investigators do look for evidence that the study treatment might be useful in a phase I clinical study.
Sources:
- Brunckhorst MK, et al. AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer. Cancer Biol Ther. 2012 Jul 1;13(9). [Epub ahead of print] PMID: 22669575.
- AT-406 Clinical Trial Protocol Summary: A Phase I, Open Label, Multi-Center, Dose Escalation Study of the Safety, Tolerability, Pharmacodynamic and Pharmacokinetic Properties of Orally Administered AT-406 in Patients With Advanced Solid Tumors and Lymphomas; ClinicalTrials.gov Identifier: NCT01078649.
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