PROJECT SUMMARY

Myelodysplastic syndromes (MDS), which primarily affect older individuals, are blood cancers that impede the body’s ability to produce blood cells, leading to symptoms such as anemia and infections. MDS are associated with relatively poor prognoses. The primary treatment for MDS is therapy with hypomethylating agents (HMAs), but in many patients, the disease eventually develops resistance to these agents and progresses. MDS patients whose disease develops such resistance have particularly poor outcomes, with a median survival duration of only 4–6 months. Clearly, new treatments for MDS patients who failed HMA therapy are urgently needed. Abnormal MDS stem cells are the cause of disease progression, but how these cells contribute to therapy failure remains largely unknown, thus delaying the design of new therapies. Our previous studies elucidated these MDS stem cells’ biological properties and revealed vulnerabilities in the disease that could be therapeutically targeted to stop its evolution.

In our recent analysis of 250 bone marrow samples from MDS patients, we found that MDS can be divided into two distinct biological subgroups. In each of these subgroups, a different MDS stem cell population expands during disease progression after HMA therapy failure. Using novel sequencing technologies to analyze these two stem cell populations, we found that disease progression in each of the two MDS subgroups was caused by a different molecular mechanism; we also identified a list of potential therapeutic targets in each subgroup. Among these targets, BCL2, a protein that promotes cell survival, was highly expressed by stem cells from only one of the two MDS subgroups. These results suggest that the stem cells in one of the two MDS subgroups could be eliminated by administering venetoclax, a novel drug that blocks BCL2’s ability to promote MDS stem cell survival. In testing this hypothesis, we found that venetoclax effectively induces the death of the stem cells from one of the two MDS subgroups in cell culture systems and animal models. Moreover, we found that venetoclax-resistant MDS stem cells are sensitive to the combination of venetoclax plus a drug that targets MCL1, a protein similar to BCL2. These results are very important because they may help the classification of MDS patients into clinical trials of venetoclax and assist in the development of other treatment approaches for MDS patients who are resistant to the therapy with venetoclax. Importantly, a clinical trial of venetoclax in combination with HMA therapy in MDS patients with disease progression after the failure of previous therapy is now underway at MD Anderson, offering an unparalleled opportunity for improving patient outcomes.

Currently, we cannot: 1) predict which patients will or will not benefit from this therapy; 2) understand why some patients respond to the therapy and others do not; and 3) know how to treat patients who do not respond to this therapy or whose disease has failed this therapy. To respond to these questions, we propose to: 1) analyze the biological and genetic differences in the stem cells and other bone marrow cells between MDS patients who respond or do not respond to venetoclax in the context of the clinical trial; and 2) determine whether venetoclax-resistant MDS patients respond to the combination of venetoclax with a drug targeting MCL1.

Because it integrates basic and clinical research to answer fundamental questions about one of the most promising therapies for MDS patients with disease progression, the proposed work has the potential to improve the outcomes of MDS patients in whom previous therapies have failed and accelerate the pace of MDS drug discovery.