433581 High-Throughput Amikagel Platform for Identification of Synergistic Treatments Against Tumor Dormancy

Wednesday, November 11, 2015: 9:06 AM
151D/E (Salt Palace Convention Center)
Taraka Sai Pavan Grandhi1, James Faust2, Thrimoorthy Potta3, Indrani Deshpande1 and Kaushal Rege4, (1)Biomedical Engineering, Arizona State University, Tempe, AZ, (2)School of Life Sciences, Arizona State University, Tempe, AZ, (3)Marlyn Nutraceuticals, Tempe, AZ, (4)Chemical Engineering, Arizona State University, Tempe, AZ

United States statistics show prostate cancer (PCa) as one of the leading cancers in male population in 2014 and causing an estimated 30,000 deaths [1]. A significant proportion of patients experience cancer metastasis to distant secondary disease sites such as bone. PCa shows unique tropism towards bone [2]; almost 66% of PCa patients experience bone metastases in some form or other, making it a crucial prognostic factor [3]. Often in these cases of prostate metastasis, tumor cells initially undergo prolonged periods of dormancy, which are followed by relapse [4]. Increasing evidence points towards a definitive phase of prolonged G0/G1 arrest rather than balanced proliferation to support prolonged viability before relapse [5]. Ablation of these cancer cell systems in their dormant state can not only eliminate the disease, but also reduce the risk of tumor relapse and death.

We have previously developed a high-throughput hydrogel system (‘Amikagel’ system) that captured prostate tumor dormancy in high-throughput. Dormant prostate cancer cells showed very high resistance to conventional cancer chemotherapeutics such as mitoxantrone and docetaxel. Here, we report that significant cell death in dormant prostate cancer cells was achieved by targeting the protein folding pathway in the endoplasmic reticulum of the cells. Targeting the endoplasmic reticulum in concert with cellular adaptations against unfolded protein response, allowed for identification of drugs that can synergize to induce dormant prostate cancer cell death. Our results suggest a new paradigm of drugs that can synergistically induce death in the dormant prostate cancer cells by targeting the endoplasmic reticulum and unfolded protein response. The talk will discuss further amplification to the synergy by modulating cellular ion levels. We show that high-throughput Amikagel platform captures tumor dormancy for large scale phenotype specific drug screens for lead identification and formulation.

[1] Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for clinicians. 2014;64:9-29.

[2] Tombal B, Lecouvet F. Modern detection of prostate cancer's bone metastasis: is the bone scan era over? Advances in urology. 2011;2012.

[3] Rigaud J, Tiguert R, Le Normand L, Karam G, Glemain P, Buzelin J-M, et al. Prognostic value of bone scan in patients with metastatic prostate cancer treated initially with androgen deprivation therapy. The Journal of urology. 2002;168:1423-6.

[4] Páez D, Labonte MJ, Bohanes P, Zhang W, Benhanim L, Ning Y, et al. Cancer dormancy: a model of early dissemination and late cancer recurrence. Clinical Cancer Research. 2012;18:645-53.

[5] Wells A, Griffith L, Wells JZ, Taylor DP. The dormancy dilemma: quiescence versus balanced proliferation. Cancer research. 2013;73:3811-6.

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See more of this Session: High Throughput Technologies
See more of this Group/Topical: Food, Pharmaceutical & Bioengineering Division