Cancers are among the leading causes of death around the world with an estimated mortality of close to 10 million in 2015, among which a total of 1,658,370 new cancer cases and 589,430 cancer deaths are projected to occur in the US alone. Particularly, breast cancer is one of the prevailing cancers among the Americans: about 1 in 8 (12%) women in the US is likely to develop invasive breast cancer during their lifetime. In 2015, estimated new cases of invasive breast cancer of 231,480 (80% invasive ductal carcinomas [IDCs]) and carcinoma in situ of 60,290 (>85% ductal carcinoma in situ [DCIS]) will be diagnosed in US women, leading to a death toll of about 40,290. Although tremendous improvements in breast cancer survival have been achieved, current drug administration procedures relying on chemotherapy followed by radiographic scans often lead to disparity in cancer care, which is largely caused by the variance in drug responses arose from intratumor heterogeneity. For example, when a presumably effective drug is administered, it requires lengthy follow-ups before the ineffectiveness of the drug and progression of the disease can be revealed. The patient will then receive an alternative drug for treatment, leading to i) accumulated systemic toxicity towards healthy organs; ii) impaired time responsiveness to the cancer which may have further progressed, rendering treatment more difficult; and iii) high cost of the treatment plan. The goal of this proposal is to tackle the aforementioned challenges by engineering and validating a multi- component ductal-carcinoma-on-a-chip platform, which recapitulates the biology and physiology of the tumor in vivo through i) construction of 3D vascularized stroma embedding perfusable, interconnected microvessels; ii) introduction of basement membrane-coated duct-like structures via bioprinting; iii) induction of progression, invasion, and angiogenesis of ductal carcinoma on the chip that recapitulates such processes in vivo; iv) establishment of a sensor-integrated platform for anti-cancer drug screening; and v) extension to a tumor-and- multi-organ-on-a-chip platform for proof-of-concept investigation of systemic drug effect. The efficacy of this platform will be validated in animal (mouse) patients. This innovative platform is expected to be clinically transformative in the future in building personalized chips through application of patient-derived cells.

Public Health Relevance

While breast cancer is one of the prevailing cancers among the Americans, a significant portion of the patients with breast cancers is diagnosed as ductal carcinomas. The drug administration process for breast cancer patients is time-consuming and often inefficient, largely due to intratumor heterogeneity and systemic side effects, which often lead to differential responses towards anti-cancer drugs. In order to tackle this issue, a microfluidic platform will be engineered to recapitulate the microenvironment of ductal carcinoma and its progression, invasion, and angiogenesis. Biosensors will be integrated to probe its responses to various anti- cancer drugs. Such platform, when fabricated using patients' own biopsied tumor cells and combined with a multi-organ platform, will ultimately enable personalized screening of anti-cancer drugs for individual patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Zahir, Nastaran Z
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Brigham and Women's Hospital
United States
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