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By Ruinan Yang and Ram I. Mahato

Ruinan YangRam MahatoProstate cancer is one of the most common cancer types and the second leading cause of cancer-related death in American men. Although several types of hormone therapy (or androgen deprivation therapy) as first line treatments are effective for prostate cancer in early stage, the shrunken tumors might become androgen-independent after 18 to 24 months of treatment leading to aggressive and metastatic forms of prostate cancer, also known as hormone refractory prostate cancer (HRPC). Taxane (docetaxel and paclitaxel), used as chemotherapy, is one of the standard therapies for HRPC. Although this anticancer agent has shown significant efficacy at initial stage of chemotherapy, the long-term efficacy is limited and patients will suffer from relapse owing to the development of chemoresistance.

One notable molecular mechanism behind chemoresistance is related to the presence of cancer stem cells (CSCs). CSCs, a rare and distinct subset of cancer cells, have stem-cell-like properties such as self-renewal/differentiation, and tumorigenic potentials, which are responsible for cancer initiation, maintenance, and relapse. The birth of cancer-stem-cell theory can be traced back to 1994. John Dick, a Canadian scientist, strikingly identified the leukemia stem cell in human leukemia and inaugurated a new era of cancer research. With decades of further development, it has been established that CSCs are found in many other types of cancer including breast, ovary, prostate, pancreas, colon cancer, and melanoma. Therefore, specific therapies targeting CSCs are essential to improve survival rate of current treatment for HRPC.

A growing body of evidence suggests that several molecular signaling pathways such as Sonic Hedgehog signaling, Notch signaling, and Wnt/β-Catenin signaling are involved in the initiation and development of CSCs. Meanwhile, microRNAs (miRNAs), a class of non-coding RNAs, have been reported to regulate tumorigenic and metastatic potentials of CSCs. They are recognized as master regulators of the genome by modulating multiple cellular pathways as well as ten to hundreds of gene expressions. Furthermore, numerous deregulated miRNAs are implicated in the pathogenesis of cancer including prostate cancer. These miRNAs can be up-regulated, known as oncogenic miRNAs, promoting cancer progression and also can be down-regulated, known as tumor suppressor miRNAs, inhibiting cancer progression. Since expression profiles of miRNAs in prostate tumors are tissue-specific, miRNAs could be not only an ideal class of biomarkers for prostate cancer detection but also promising targets for therapy.

These findings give us better idea of how to utilize the correlation between miRNAs and CSCs to target and kill CSCs, thereby more effectively inhibiting growth and metastasis of prostate cancer. We hope to have one potent and multi-functional anticancer drug that is not only able to kill the bulk of the tumor but also be capable of targeting CSCs and interfering miRNA expression. In practice, current cancer therapy might achieve this vision through combination therapy, i.e., combining an anticancer drug and CSC inhibitor. Even though there are pending problems like how to design a suitable delivery system to carry two hydrophobic drugs (most anticancer drugs are hydrophobic) and simultaneously deliver and release them to the same tumor site, the combination therapy of CSCs inhibitor and tumor-mass inhibitor has shown great potentials for drug-resistant prostate cancer treatment.

This work is being presented at the 2015 AAPS Annual Meeting and Exposition this week in Orlando.

Ruinan Yang, M.S., is a graduate student in the Department of Pharmaceutical Sciences at the University of Nebraska Medical Center. Her interested research area is micelles and nanoparticles for drug delivery in cancer treatment.
Ram I. Mahato, Ph.D., is a professor and chairman of the Department of Pharmaceutical Sciences at the University of Nebraska Medical Center. His research is focused on drug delivery, siRNA/miRNA/gene delivery, and polymer synthesis.