MERIT Award Recipient: Brian Druker, M.D.
|Sponsoring NCI Division:||Division of Cancer Biology (DCB)|
|Award Approved:||February 2011|
|Institution:||Oregon Health & Science University|
|Department:||Division of Hematology/Medical Oncology|
|The Druker Lab|
Chronic Myelogenous Leukemia and BCR-ABL Substrates
Cancer is a disease in which the malignant cells proliferate uncontrollably. Traditional chemotherapy kills dividing cells indiscriminately, leading to side effects and limiting efficacy. Our goal has been to identify the precise abnormality that drives the growth of a cancer and to use this information to exclusively target cancer cells.
We dramatically demonstrated the power of targeted cancer therapy in the treatment of chronic myeloid leukemia (CML). All patients with CML carry the same molecular defect, an enzyme called BCR-ABL, which instructs CML cells to multiply in an uncontrolled fashion. BCR-ABL is present in CML cells but not in normal cells, providing a selective target for therapy within these cancer cells. Imatinib (Gleevec) is a drug that impairs BCR-ABL activity, and imatinib-based therapy has been the first-line CML treatment for a decade. Imatinib has completely reversed the prognosis for patients with CML from a disease with a life expectancy of less than 5 years to a disease that now has a 95% five-year survival.
Many obstacles remain in CML, and these same issues are projected to surface for all cancers treated with targeted therapy. The emphasis of this MERIT award is to deepen our knowledge of targeted therapy in CML such that all patients with this disease as well as forthcoming cancer patients on new gene-targeted therapies benefit from our findings. The first issue we are confronting is resistance to targeted therapy (in the case of CML, imatinib). This problem has largely been traced to acquired mutations within the BCR-ABL protein that prevent imatinib from binding to BCR-ABL. An enormous research effort has provided a detailed molecular understanding of this resistance mechanism, culminating in the design of new inhibitors such as nilotinib (Tasigna) and dasatinib (Sprycel), which have benefited many patients with CML. A singular mutation within BCR-ABL (termed T315I), however, remains insensitive to all approved drugs, exposing a critical gap in clinical coverage for patients with CML. We are investigating inhibitors whose target profiles encompass the T315I mutation, including the clinical candidates ponatinib (AP24534) and DCC-2036. Furthermore, some patients are resistant to imatinib therapy with no identifiable BCR-ABL mutations. To establish the molecular basis for this BCR-ABL-independent mechanism of disease resistance and to identify new therapeutic targets, we are integrating a variety of functional and genome-wide analytical techniques. Beyond improving treatment strategies for CML, we expect this knowledge to impact treatments for other cancers as the targets we identify are likely to be driving the uncontrolled growth of other cancers.
A second aim of our studies is to investigate fundamental properties of BCR-ABL inhibitor efficacy. A fundamental principle in the use of BCR-ABL inhibitors has been that sustained target inhibition is required for success. Although this is the case with imatinib, a surprising clinical observation arose in the clinical trials of dasatinib, which is effective despite only transient inhibition of BCR-ABL. This challenges the dogma of continuous inhibition and we are conducting detailed studies of the properties that BCR-ABL targeted therapies must possess to kill CML cells. These results will influence inhibitor therapy for CML and may radically alter design principles for targeted cancer therapeutics.
Despite the impressive success of targeted therapies in the treatment of CML, substantial evidence suggests that CML stem cells, the root of the disease, are not fully dependent on BCR-ABL and probably cannot be eliminated by inhibiting BCR-ABL. Consequently, BCR-ABL inhibitor therapy is generally not curative and patients must take medication indefinitely. To develop innovative, CML cell-selective targeting strategies, we have initiated a systematic investigation of the structural basis for activation and regulation of BCR-ABL. This knowledge may facilitate targeting of CML stem cells, a capability that would open the possibility of disease eradication.
Taken together, our studies address several major aspects of targeted cancer therapy: drug resistance due to mutation or activation of alternative pathways, fundamental mechanisms of oncogene dysregulation, and the inability of targeted therapies to kill cancer stem cells. As treatment of CML serves as a paradigm for targeted cancer therapy, the knowledge gained from these studies will benefit patients with CML and other malignancies.