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Breast Cancer Research Foundation-AACR Career Development Award for Translational Breast Cancer Research

The Breast Cancer Research Foundation-AACR Career Development Awards for Translational Breast Cancer Research represent a joint effort to promote and support innovative research designed to accelerate the discovery, development, and application of new agents to treat breast cancer and/or for preclinical research with direct therapeutic intent. Eligibility is limited to a junior faculty who has completed their most recent doctoral degree or medical residency within the past 11 years. The research proposed for funding must be translational in nature and must have direct applicability and relevance to breast cancer.

2017 Grantees

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Bryan R. Smith, PhD
Instructor
Stanford University
Stanford, California
Treatment enhancement via specific manipulation of tumor immunosuppression

Scientific Statement of Research
Recent research has robustly demonstrated that the efficacy of current and emerging cancer treatments is hindered by tumor-mediated immunosuppression effects. Myeloid-derived suppressor cells (MDSCs) play a key role in the maintenance of an immunosuppressive tumor microenvironment that facilitates tumor growth and treatment resistance. We propose to build upon previous work in the nanoprecipitation of albumin-based, drug-loaded nanoparticles (NP) by adding biologic targeting agents to preferentially accumulate NP in myeloid cells. By delivering a payload that is preferentially active in MDSCs, we will specifically inhibit MDSC function, thereby leading to restoration of a competent anti-tumor immune response and increased treatment sensitivity. Our proposed nanoparticle platform was deliberately designed to ease translation. Re-use of FDA-approved drugs in a well-characterized NP architecture and formulation process ensures regulatory familiarity, availability of clinical-grade components, and known safety and side effect profiles.

Biography
Dr. Smith is an instructor in the Department of Radiology and the Molecular Imaging Program at Stanford (MIPS) at Stanford University. He received bachelor's degrees in physics, mathematics, and biomedical engineering. He was awarded a doctorate at The Ohio State University in biomedical engineering as an NSF predoctoral fellow. At Stanford, Dr. Smith has received many awards and published dozens of nanomedicine and oncology articles in journals ranging from Nature Nanotechnology and Nano Letters to Cancer Research and PNAS and has several patents issued and pending. His lab focuses on the development of nano-enabled immuno-imaging and immunotherapy platforms.

Acknowledgement of Support
The 2017 Breast Cancer Research Foundation-AACR Career-Development Award for Translational Breast Cancer Research will be invaluable for my career. It jump-starts my nano-immunotherapy program, making possible data to drive future immuno-oncology grants. More importantly, it fast tracks my team’s passionate interest in rapidly getting our technology to the clinic.

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Tal Danino, PhD
Assistant Professor
Columbia University
New York, New York
Enhancing breast cancer immunotherapies with engineered probiotics

Scientific Statement of Research
This proposal uses novel approaches from synthetic biology to genetically program probiotics to safely deliver therapeutics for breast cancer. Due to their unique property in selectively colonizing tumor necrotic cores, probiotic bacteria can act as specific vehicles for the localized delivery of therapeutics. We will use the probiotic E.coli Nissle 1917, which has been widely and safely tested in humans, to deliver immunotherapeutics to breast cancer metastases. Several therapeutics from the field of immunotherapy will be tested that either activate or recruit the immune system, and efficacy and safety will then be assessed in breast cancer mouse models.

Biography
Tal Danino is an assistant professor of biomedical engineering and leads the Synthetic Biological Systems Laboratory at Columbia University in the City of New York. He received a PhD in bioengineering from the University of California, San Diego, focused on synthetic biology, and completed his postdoctoral training at the Koch Institute for Integrative Cancer Research at MIT where he developed the use of bacteria to detect and treat cancer. In addition to his research, Dr. Danino also brings science outside the laboratory as a TED fellow and through science-art and outreach projects.

Acknowledgement of Support
I am greatly honored to receive the Breast Cancer Research Foundation-AACR Career Development Award. I hope that this award will help build a research framework for engineering probiotics to safely and effectively deliver  immunotherapeutics for metastatic breast cancer. 

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2016 Grantees

Brooke M. Emerling, PhD
Assistant Professor
Sanford Burnham Prebys Medical Discovery Institute
La Jolla, California
Targeting PI5P4K for triple negative breast cancer therapy

Triple negative breast cancer (TNBC) accounts for 15-20 percent of breast cancers. Women with TNBC are three times more likely to experience death compared to other subtypes. Mutations in the tumor suppressor gene TP53 (encoding p53) are found in the vast majority of TNBC. Although TP53 mutations are found frequently in TNBC, it is difficult to target p53-deficiency with drugs. The poor prognosis of TNBC can be attributed to the lack of effective targeted therapy. We recently identified a novel "druggable" class of phosphoinositide kinases, the phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks), whose loss of function results in synthetic lethality with p53 loss. Prior to this observation of this synthetic lethality, these enzymes were not a focus for oncology research.

The PI5P4K enzymes phosphorylate the 4 position of phosphatidylinositol-5-phosphate to generate phosphatidylinositol-4,5-bisphosphate, the substrate utilized by phosphoinositide-3-kinase (PI3K) for generating phosphatidylinositol-3,4,5-triphosphate, the second messenger that activates AKT. We have shown that by knocking down both PI5P4Kα and PI5P4Kβ in p53 deficient breast cancer cell lines, we can block the growth on plastic and in xenografts. This impaired growth correlates with reduced glucose metabolism and disrupts efficient autophagy. Importantly, we found that germline deletion of both Pip4k2a and Pip4k2b (the genes encoding for PI5P4Kα and PI5P4Kβ) in mice suppresses tumor formation with TP53 deletion, thereby suggesting that targeting these enzymes with novel agents will prevent the growth of TNBC that have p53 mutations. Our hypothesis is that the PI5P4K enzymes provide a back-up to TP53 in regard to mediating responses to metabolic stress and that these enzymes only become critical when p53 function is lost.

Using preclinical studies in novel genetically engineered mouse models and in human TNBC cell lines we will address whether targeting these enzymes will be an effective therapy for TP53 mutant breast cancers, especially the TNBC subgroup where targeted therapies have not been effective. Successful completion of this work will contribute significantly to our understanding of p53 deficient TNBCs, as well as will set the trajectory for future work aimed at guiding the development of clinical treatment strategies for TNBC.

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Wenqi Wang, PhD  
Instructor, Department of Experimental Radiation Oncology
University of California, Irvine
Irvine, California
Targeting the Hippo-YAP pathway for breast cancer treatment

Breast cancer can be divided into biologically distinct subtypes based on their genetic profiles.  Treatment decisions are being made based on the available information of driver genes. However, breast cancer heterogeneity highlights the need for additional investigations to further understand the biology of this disease and design appropriate treatment plans. If we better understand both the oncogene and non-oncogene addictions of breast cancer, which convey the hallmarks of oncogenesis, we can improve the outcome for patients with biologically distinct subtypes.
The Hippo pathway has been established as a tumor suppressor pathway because it restricts proliferation and induces apoptosis. As the key effector, YAP is phosphorylated and inactivated by the Hippo pathway. In the past few years, Dr. Wenqi Wang has been devoted to studying the role of Hippo-YAP pathway in cancer development and its translational potential for cancer therapy. In his proposed study, Dr. Wang plan to explore YAP as a potential target for breast cancer treatment.

YAP is known to function as an oncogene and induce cell proliferation and tumorigenesis. Many studies have demonstrated the crucial roles of YAP in breast cancer development via its abilities to transform normal mammary epithelial cells, accelerate breast cancer cell proliferation and survival, maintain breast cancer stem cells, and promote breast cancer metastasis. These findings suggest that YAP is a potential target for breast cancer treatment. However, the development of compounds targeting YAP in breast cancer has been slow and limited. So far, there is no option to pursue this pathway in clinical settings.

Dr. Wang proposed a novel oncogenic function of YAP in breast cancer metabolism that has yet to be recognized. He will further reveal the oncogenic functions of YAP in breast cancer metabolism and inspire the development of therapeutic tools targeting YAP for breast cancer treatment. Moreover, his pilot compound screen uncovered some clinical compounds as bona-fide inhibitors for YAP and his proposed in-depth mechanistic studies underscore the translational potential of targeting YAP for breast cancer therapy.

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2015 Grantees

Sasha Elizabeth Stanton, MD, PhD  
Acting Instructor, Medicine
University of Washington
Seattle, Washington
Development of a multi-antigen vaccine for breast cancer prevention

Ductal carcinoma in situ (DCIS) is the most common premalignant breast lesion with over 60,000 women diagnosed each year. Not all DCIS will develop into invasive cancer, however, it is difficult to predict which DCIS lesions will become invasive, therefore, all DCIS is treated aggressively with surgery, radiation, and even cytotoxic chemotherapy. Vaccine therapy for DCIS could improve current therapy options because a vaccine given when a woman is diagnosed with DCIS would (1) provide a therapy that can induce durable long term protection of both recurrent DCIS and progression to invasive breast cancer (IBC) (2) provide a therapy that is infrequently dosed and therefore easier to maintain long term compliance (3) provide a therapy that typically is well tolerated and that may allow certain patients to avoid the risks of surgery, radiation, and chemotherapy. Previous studies in our laboratory have demonstrated that vaccination against proteins overexpressed in DCIS can prevent development of IBC in a transgenic mouse mammary tumor model TgMMTV-neu which is genetically similar to human luminal breast cancer and progresses through a pre-invasive stage similar to DCIS. We now aim to expand on these early successes and develop a vaccine using proteins that are aberrantly overexpressed in DCIS and are biologically relevant to disease progression. 

Hypothesis: We hypothesize that immunization with a multi-antigen polyepitope vaccine targeting functionally relevant overexpressed proteins in DCIS that are also present in IBC will increase the Th1/CD8 cytotoxic T cell immune response against pre-malignant DCIS lesions preventing recurrence of the pre-malignant disease and progression to IBC. (1) Identify possible DCIS antigens that are overexpressed in both DCIS and IBC, functionally relevant to cancer cell survival, and are immunogenic in early breast cancer patients, (2) Define epitopes that will selectively stimulate the anti-tumor Th1 CD4+ T cell response and exclude the suppressive Th2 CD4+ T cell response and (3) Determine if the vaccine is immunogenic, non-toxic, and can prevent progression of DCIS to IBC in transgenic mice.

A multi-antigen vaccine targeting important pathways in DCIS could provide a safe and effective approach for prevention of recurrent DCIS or progression to invasive breast cancer. 

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