Approximately 90% of all deaths from breast cancer arise from metastatic spread of a primary tumor. The failure of current cancer treatment may be explained by a small subset of therapy-resistant and highly metastatic cancer stem cells (CSCs). Although experimental and clinical studies have demonstrated the presence of CSCs within breast and other solid tumors little is known about CSCs that can disseminate by blood circulatory system to distant sites, forming metastases. The major obstacle is technical limitations (e.g., low sensitivity) of current assays to identify rare stem CTCs among a small population of CTCs disseminated in a large background of different blood cells in flow. The overall goal of this proposal is in vivo molecular targeting, quantitative detection, enrichment and elimination of stem CTCs using integrated high sensitivity laser methods and novel, multifunctional low-toxic nanoparticles. We will accomplish this goal through the following specific aims:
Specific Aim 1 : Develop an integrated multispectral high-sensitivity photoacoustic/photothermal (PA/PT) platform with multifunctional PA/PT nanoprobes for multipex molecular detection, enrichment and elimination of breast stem CTCs. The technological platform for stem CTC research in vivo will be developed by integration of three innovative approaches: 1) highly sensitive, deeply penetrating and noninvasive laser photoacoustic (PA) techniques;2) biocompatible functionalized hybrid gold-magnetic nanotubes (GMNTs);and 3) laser photothermal (PT) elimination of stem CTCs.
Specific Aim 2 : Estimate diagnostic and therapeutic capability of new platform for detection and elimination of stem CTCs naturally shedding from a parent tumor using a mouse model of human breast cancer. The quantitative detection and magnetic enrichment of stem CTCs in vivo will be developed in order to understand significance of stem CTCs for metastases initiation and progression and to provide a novel approach for effective molecular targeting and laser elimination of stem CTCs resistant to conventional therapies. In general, the combined use of in vitro (Aim 1) and in vivo (Aim 2) PA/PT-nanoparticle strategies should verify a proof-of-concept for the role of cancer stem CTCs in breast cancer. Taking into account the safety of using laser and gold-based nanoparticles, we predict that proposed approach can be translated quickly to patients with any metastatic cancers by development of a portable wrist device for patient's CTC diagnosis and treatment.
The relevance to the public health of achieving this goal derives from the potential of this technology to allow the routine in vivo biomonitoring of circulating cancer cells as early markers for micrometastatic development and cancer recurrence in cancer patients, as well as evaluation of the efficacy of radiation therapy, laser therapy, and chemotherapy. A robust, low-cost, portable, safe for humans medical device for routine daily use (if necessary) can be developed and envisioned in various clinical scenarios: (1) classifying most patients'tumors into high- and low-risk-metastatic categories;2) optimizing a conventional therapeutic regimen to achieve decreased toxicity and maximum efficacy by permitting the assessment of the clinical response through the counting of circulating cancer stem cells;(3) diagnostic with periodic laser blood purging, to reduce risk of metastasis development, especially when a tumor is resistant to standard chemotherapy or radiation therapy;(4) the early diagnosis of cancer when there is parallel progression of a primary tumor and the appearance of circulating cancer cells;and (5) the assessment of sentinel nodes and surgical sites before and after tumor removal for margin evaluation and detection of residual cells, respectively.
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