Arsenic-based therapy shown to help eradicate leukemia-initiating cells
BOSTON -- In both leukemiaterm and solid tumors, there exists among the multitude of warrior cancer cells a small subgroup that work undercover, patiently lying in wait to launch their attacks. Known as either cancer initiating cells (CICs) or leukemia initiating cells (LICs), these stealth populations are impervious to conventional chemotherapyterm and undaunted by targeted cancer therapies. When a leukemia patient relapses following a period of remission, it is the LICs that bear responsibility for the diseaseâ€™s reemergence.
The secret to the survival abilities of these cells has been unclear. But in a paradoxical discovery, a research team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has found that a tumor suppressor protein known as PML appears to be the factor that enables LICs to maintain their quiescence â€“ the inert state that protects them from being destroyed by cancer therapies â€“ and suggests that inhibition of PML is a promising target for new therapeutics.
Their findings, which appear in todayâ€™s advance on-line issue of the journal Nature, additionally demonstrate that PML can be degraded with an arsenic-based agent used in traditional Chinese medicine. Importantly, when combined with chemotherapy, the arsenic-based therapy -- already proven safe and non-toxic in clinical trials -- can successfully treat chronic myeloid leukemia.
â€œLeukemia initiating cells share many properties of normal hematopoetic stem cells,â€ explains senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Genetics Program in BIDMCâ€™s Cancer Center and Professor of Medicine and of Pathology at Harvard Medical School. â€œThey are pluripotent, they readily replicate and they can indefinitely remain in a dormant state of quiescence.â€
Consequently, while the majority of leukemic cells are vulnerable to any cancer therapies â€“ including chemotherapy and targeted cancer treatments â€“ that destroy cells during active DNA replication, LICs, with their unique quiescent properties, resemble an automobile with an endless supply of fuel and a sturdy set of brakes: They sit quietly idling in place, waiting to reinitiate malignancy after a period of remission.
Pandolfiâ€™s laboratory has been working to develop new therapeutic approaches to target LICs and thereby treat chronic myeloid leukemia (CML), one of the most extensively investigated of stem cell disorders. CML is typically treated with the targeted therapy imatinib (Gleevec), a tyrosine kinase inhibitor.
â€œGleevec does dramatically improve prognosis of CML patients,â€ notes Pandolfi. â€œBut, unfortunately, Gleevec is not curative in most cases. Because it targets only dividing cells, the pool of quiescent LICs are able to remain intact.â€ As a result, when Gleevec therapy is discontinued, the cancer almost inevitably relapses.
The investigators set out to analyze expression of PML, a tumor suppressor protein that controls fundamental processes such as apoptosis, cellular proliferation and senescence. PML is commonly associated with acute promyelocytic leukemia (APL), in which it leads to the formation of a fusion protein that blocks cell differentiation.
After ascertaining that PML was highly expressed in the LICs of a CML mouse model, Pandolfiâ€™s team also determined that PML is highly expressed in blasts from CML patients and that low PML levels corresponded with patientsâ€™ increased response to therapy and overall survival rates.
â€œWe then analyzed LIC function in the absence of PML and revealed that PML has an indispensable role in maintaining LIC quiescence,â€ he adds. â€œAs a result, PML-deficient LICs grow exhausted over time, becoming incapable of generating CML in the transplanted animals.â€
Lastly, the investigators examined the impact of As2O3, an arsenic-based therapy that targets PML for degradation and is currently used for the treatment of acute promyelocytic leukemia. As predicted, inhibition of PML by As2O3 successfully disrupted LICs, increasing the efficacy of the anti-cancer therapy by sensitizing the LICs to pro-apoptopic stimuli.
â€œItâ€™s actually a very simple concept,â€ says Pandolfi. â€œNinety percent of existing cancer treatments are antiproliferative agents â€“ they target the pool of proliferative cells, leaving behind the dormant LICs.
â€œBut in determining that PML serves to guard the LICs that have been left behind, we also discovered that if we knock out PML [through pharmacologic means], the LICs will lose their braking abilities and run out of gas, thereby commiting the fatal error of proliferation -- and exposing themselves to the deadly effects of cancer therapies.â€
Pandolfiâ€™s laboratory is now trying to determine whether PML exerts a similar role in the stem cells of other tissues, as well as in the cancer initiating cells of solid tumors.
â€œIf this turn out to be the case,â€ he adds, â€œthe transient use of As2O3 may represent a more global strategy to target CICs in other forms of cancer.â€