Moffitt Researchers Target Cellular Process to Improve Multiple Myeloma Outcomes

Understanding the complex often starts with examining the basics. This approach has helped scientists from across many fields tackle the most challenging problems facing humanity, including cancer research. At Moffitt Cancer Center, Dr. Marilena Tauro, research scientist in the Tumor Biology Department, and her team have taken this stance by focusing their efforts on understanding how a cellular process, called autophagy (pronounced aw-TAH-fuh-gee), impacts treatment options for those with multiple myeloma and what new therapies may be introduced to help patients overcome chemotherapy resistance.

In this article, we break down the science in five questions with Tauro.

What is autophagy and what role does it play in the treatment of multiple myeloma?
Autophagy, stemming from Greek meaning “self-devouring,” is a physiologic mechanism that allows our body to break down and reuse old cell parts so our cells can operate more efficiently. It’s a natural recycling process that begins when cells are stressed or deprived of nutrients. Recent scientific advances support that this cellular survival system is also adopted by certain cancer cells, especially when they need to survive in the face of harsh conditions, such as starvation, radiation and exposure to chemotherapy.

Multiple myeloma is a type of blood cancer characterized by the abnormal growth of malignant plasma cells in the bone marrow, causing bone destruction, elevated blood calcium levels, anemia and renal dysfunction over time.

In multiple myeloma, autophagy has been shown to support cancer cell survival and drug resistance by removing the effects of chemotherapy drugs. This allows cancer cells to persist and continue to grow despite therapy. Hence, targeting autophagy should be considered a potential strategy for overcoming drug resistance and improving the effectiveness of treatment for multiple myeloma.

What is the relationship between autophagy and chemotherapy resistance? 
Cancer therapy works by inducing cell death and inhibiting cancer cell survival. Unfortunately, certain cancer cells that are initially killed by treatment can activate survival mechanisms and adapt to withstand previously used drugs. This phenomenon is referred to as chemotherapy resistance and is a major challenge for oncologists as it limits the effectiveness of currently available anticancer drugs.

Multiple myeloma cancer cells protect themselves by inducing autophagy, which markedly reduces the efficacy of current drugs and makes them unaffected by chemotherapy. Understanding the mechanisms behind chemotherapy resistance is important because a significant number of patients with multiple myeloma will become resistant to treatment and experience relapse within five years of diagnosis.

Tell us about your research study. What were the findings and was there a difference between newly diagnosed and relapsed patients? 
Our group discovered that autophagy in multiple myeloma cells is mediated by a novel protein called ULK3, and this protein’s levels increase as the disease progresses. Patients that become resistant to chemotherapies show higher levels of autophagy and ULK3 protein. We believe this novel protein can represent a biomarker for multiple myeloma.

In collaboration with Dr. Nicholas Lawrence, a senior member in the Drug Discovery Department, and his research lab, we designed and characterized small molecules that can inhibit the activity of ULK3 and therefore the autophagic survival mechanism, resulting in cancer cell death.

We are currently optimizing the drug profile of these inhibitors, and we believe that the combination of selective ULK3 inhibitors with standard of care chemotherapy represents a potential strategy in overcoming treatment resistance in multiple myeloma patients.

Our preclinical studies showed promise in limiting tumor burden and increasing overall survival. Importantly, we noted no overt toxicity and protected effect against myeloma-induced bone disease. Results showed that ULK3 inhibitors are potent both as single agents and in combination with standard of care therapeutics, not only in the newly diagnosed patients, but also in relapsed and treatment resistant patients.

What are the next steps in your research? 
We are currently directing our research focus on developing novel selective molecules to inhibit ULK3-mediated autophagy and we anticipate we will be able to include novel molecules in clinical practice soon. We are also assessing this treatment strategy in other malignancies, and we look forward to expanding the applicability of such new scientific discoveries.

What might the findings mean for the standard of care for multiple myeloma?
We identified a novel mechanism that cancer cells use to become resistant to chemotherapy: ULK3-mediated autophagy. The development of this new treatment strategy will lead to optimized molecules that could be used in combination with standard of care therapies to enhance their efficacy and improve patients’ response to treatment.