Our Goal: Reinventing a Cornerstone of Cancer Treatment with the Intent to Provide Safer and More Effective Chemotherapy
Chemotherapy continues to be a cornerstone of cancer therapy. Despite the progress made with immunotherapy and precision medicine, the first-line treatment for many cancers continues to include chemotherapy. Cumulative research data now allow for a better understanding of the mechanisms of anticancer activity as well as toxic side effects, providing the opportunity to design and develop improved chemotherapeutic agents that may be safer and more effective. Annamycin is an anthracycline designed with this purpose in mind. Anthracyclines are a class of chemotherapy drugs considered to be among the most effective available, and with a broader spectrum of anticancer activity than most other classes of chemotherapeutic agents. They are recognized for their pleiotropic (producing or having multiple effects) mechanisms of action and for DNA being their primary target. In particular, anthracyclines interfere with an enzyme called “topoisomerase II,” resulting in damage to the DNA of rapidly replicating tumor cells. Such DNA damage leads to tumor cell death in a process called “apoptosis” (programmed cell death).
Acute leukemia (including both AML and ALL) is among a number of cancer types that usually are treated with anthracyclines. In the case of acute leukemia, anthracyclines are typically used in “induction therapy,” where the goal is to induce sufficient remission of patients’ tumor cells to allow for a curative bone marrow transplant.
Two key factors limit the safety and effectiveness of currently approved anthracyclines: cardiotoxicity (potential to damage the heart) and multidrug resistance. Annamycin shows promise to possibly overcome these two factors; if preliminary data are borne out, Annamycin may ultimately provide clinically meaningful benefits over currently approved anthracyclines in treating certain cancers. Preliminary data from very early-stage clinical trials suggest acute leukemia as a potentially opportune indication in which to further study Annamycin.
One of the key dose-limiting toxicities associated with currently available anthracyclines (including the anthracycline in the recently approved drug, Vyxeos) is the propensity to induce life-threatening heart damage. This is a particularly significant risk for pediatric leukemia patients, whose life spans can be severely shortened by the induction therapy intended to cure them of acute leukemia. In the animal model recommended by the FDA as an indicator of human cardiotoxicity, the non-liposomal (free) form of Annamycin has been shown to be significantly less likely than doxorubicin to create heart lesions in mice, and the liposomal formulation (L-Annamycin) has been shown in these same models to have reduced cardiotoxicity to the point where it is unlikely to cause harm to human patients. If this characteristic is shown to be the same in humans, it may allow L-Annamycin to be used more aggressively to help patients achieve remission. This would be especially valuable in the case of pediatric acute leukemia (both AML and ALL) because of the potential impact of cardiotoxicity on long-term survival. In our current Phase I/II trial for Annamycin, we are collecting data to further validate the design intent of Annamycin to have little or no cardiotoxicity. Unless otherwise noted, all of our references to Annamycin refer to the liposomal form (L-Annamycin).
In addition, the effectiveness of currently approved anthracyclines is limited by their propensity for succumbing to “multidrug resistance.” This can occur where, as a natural defense mechanism, transmembrane proteins acting as transporters (one type of which is referred to as a “P-glycoprotein pump” or “ABCB1 transporter”) develop on the outer surface of cells to expel drugs like anthracyclines. In many instances, the likelihood of cardiotoxicity (and other serious side effects) prevents increasing the dosing of current therapies in order to overcome multidrug resistance. As a result, most patients cannot receive current anthracyclines in doses that are adequate to produce lasting remission and thereby qualify for a bone marrow transplant. A laboratory study has suggested that Annamycin may resist being expelled by P-glycoprotein pumps and similar multidrug resistance transporters, which may mean the drug circumvents multidrug resistance. This characteristic has been shown in pre-clinical testing to allow for higher drug uptake in diseased cells, which we believe could allow for more effective induction therapy with less risk to the patient.