CaMKK2 Inhibition as an Approach to Increase Tumor Immunity in Breast Cancers
Abstract
Breast cancer is the most commonly diagnosed cancer in women and remains the second highest cause of cancer-associated deaths among women in the U.S. This underscores the urgent need to revolutionize breast cancer treatment regimens and develop novel and effective therapeutics that can significantly increase survival rates and improve the quality of life of breast cancer patients. In recent years, immunotherapy has had a profound paradigm-changing impact on cancer treatment, joining the ranks of chemotherapy, radiotherapy, surgery, and targeted therapy as a pillar of cancer treatment strategies. Indeed, the use of cancer immunotherapy has reached an important inflection point in the clinic, attaining considerable success in the management of several cancer types, including lymphocytic leukemia, non-Hodgkin’s lymphoma, melanoma, and more recently, lung cancer. It is likely that the total eradication of breast cancer will require the engagement of the host immune system acting in a spontaneous manner to eradicate cancer cells or following its manipulation with interventions that increase tumor immune responses. Notwithstanding these encouraging results in other cancers and recent approval of atezolizumab plus nab-paclitaxel combination for patients with locally advanced or metastatic PD-L1-positive triple-negative breast cancer (TNBC), approaches to improve existing immunotherapeutic modalities in this disease are still urgently needed. Established limitations to successful immunotherapies in breast cancer are poor recruitment of cytotoxic tumor infiltrating lymphocytes (TILs), lack of neoantigen diversity, and the ability of tumors to suppress immune cell function. Thus, development of facile approaches to increase the recruitment of cytotoxic TILs to tumors is anticipated to enhance tumor immunogenicity and response to contemporary immunotherapy regimens. It is significant, therefore, that we have been able to show that genetic or pharmacological inhibition of the enzyme calcium calmodulin kinase kinase 2 (CaMKK2) within tumor-associated myeloid cells/macrophages, dramatically reduces tumor burden in animal models of breast cancer, an activity that tracks with increased recruitment of activated cytotoxic TILs into tumors. Our recent data have also indicated that inhibition of CaMKK2 within breast cancer cells themselves significantly reduces their ability to disseminate to distant organs. Together, these data suggest that appropriate pharmacological targeting of CaMKK2 will have beneficial effects on tumor biology through its actions in tumor cells and within tumor-associated myeloid cells. Our data highlight the potential clinical utility of CaMKK2 inhibition in breast cancer and provide the impetus for this proposal where we will assess the efficacy of targeting CaMKK2 in combination with current standard of care therapies in clinically relevant murine models of advanced breast cancer. We also plan to identify the mechanisms by which CaMKK2 impacts processes of pathological importance in myeloid cells and in cancer cells with a view to identifying additional targetable nodes that can be exploited to enhance anti-tumor immunity and reduce/treat metastasis. Finally, the impact of manipulating the CaMKK2 signaling axis will also be evaluated in models that recapitulate the human breast cancer tumor microenvironment, the results of which, we believe, will inform near-term clinical studies of new therapeutic regimens. The primary focus of this initial work will be TNBC where we see particularly high expression of CaMKK2. However, the insights from this work we believe will also impact the pharmacotherapy of all breast cancer subtypes. This work will address the Breast Cancer Research Program overarching challenges of (1) revolutionizing breast cancer treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival and (2) eliminating the mortality associated with metastatic b
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010498
Entities
People
- Luigi Racioppi
Organizations
- Duke University
- United States Army