Using a Cancer Drug to Advance Stem Cell Therapy

By Amanda Chase, Ph.D.
June 7, 2021

Stem cells have a unique ability to develop into specialized cell types in the body and can continue to increase in numbers indefinitely. This unique ability can promote the repair of diseased or dysfunctional tissues, known as regenerative medicine or stem cell therapy.  Bone marrow transplant has long been used during certain cancer treatments, and can be classified as stem cell therapy: the transplantation of hematopoietic stem cells, usually from the bone marrow. More recently, there have been rapid advances in pluripotent stem cells (PSCs), which are made up of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) that has allowed the expansion of the use of stem cell therapy and has allowed regenerative therapy in clinical trials. Novel methods that enabled PSD-derived cardiomyocytes (CM; heart cells) made regenerative therapy for cardiovascular disease feasible. Cardiovascular disease is often characterized by injured heart muscle (myocardium) or tissue, and regenerative therapy could be used to replace the injured myocardium and repair the injured tissue to restore function.

Despite the immense potential of stem cell therapy, there are still some important hurdles to consider. First, the clinical translation of pluripotent stem cell (PSC) derivatives is hindered by the tumorigenic risk from residual undifferentiated cells. Second, tumor growth can occur due to the cells continuing to multiply, a significant barrier to clinical trials using iPSC-CMs. Addressing these hurdles is critical for regenerative therapy to advance and move through clinical trials.   

Figure. (A) An undifferentiated ESC can multiply and lead to tumor formation. (B) When ESC-CMs are directly injected into an animal, tumors can form from any remaining undifferentiated ESCs. When the ESC-CMs are treated with a low-dose of doxorubicin before injection, there was no tumor formation because all remaining undifferentiated ESCs were removed.

A team from Stanford Cardiovascular Institute (CVI), including first author Tony Chour and senior authors Evgenios Neofytou, M.D., Senior Scientist at CVI, and Joseph Wu, M.D., Ph.D., Director of CVI, established a novel method to decrease the chance of tumor formation from cardiac stem cell therapy, recently published in JCI Insight. In the study, researchers targeted the ability of the PSCs to continue to grow and multiply using a chemotherapeutic agent called Doxorubicin. Doxorubicin is an FDA-approved drug that has commonly been prescribed for patients with cancer since the 1960s to inhibit cancer cells from growing and multiplying.

An important consideration was that doxorubicin could also be cardiotoxic, and therefore needs to be used at a dose that is both effective and non-cardiotoxic.

This minimal dose of doxorubicin exhibited no side-effects on PSC-CMs at concentrations that were toxic to undifferentiated cells and shown to be able to eliminate undifferentiated PSCs and enriched CMs during PSC differentiation cultures.

In this study, the researchers found that a low-dose of doxorubicin is both an effective and safe means to remove the stem cells that could continue to divide while leaving the ESC-CMs that are terminally differentiated and would not contribute to tumor formation. Pre-treatment of the ESC-CMs with the low-dose of doxorubicin before transplantation prevented teratoma (tumor) formation. This effective and feasible method to reduce the chances of stem cell therapy in forming tumors provides a promise to advance  stem cell therapies in cardiovascular clinical applications.

Other authors from the Stanford Cardiovascular Institute are Lei Tian, Edward Lao, Dilip Thomas, Ilanit Itzhaki, Olfat Malak, Joe Zhang, Xulei Qin, Mirwais Wardak, Yonggang Liu, Mark Chandy, Katelyn Black, and Evgenios Neofytou.  

Dr. Evgenios Neofytou