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Therapeutic efficacy of a novel ?III/?IV-tubulin inhibitor (VERU-111) in pancreatic cancer.

ABSTRACT: BACKGROUND:The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. Among various tubulins, ?III and ?IV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not readily available. METHODS:We determined anti-cancer molecular mechanisms and therapeutic efficacy of a novel small molecule inhibitor (VERU-111) using in vitro (MTS, wound healing, Boyden chamber and real-time xCELLigence assays) and in vivo (xenograft studies) models of PanCa. The effects of VERU-111 treatment on the expression of ?-tubulin isoforms, apoptosis, cancer markers and microRNAs were determined by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses. RESULTS:We have identified a novel small molecule inhibitor (VERU-111), which preferentially represses clinically important, ?III and ?IV tubulin isoforms via restoring the expression of miR-200c. As a result, VERU-111 efficiently inhibited tumorigenic and metastatic characteristics of PanCa cells. VERU-111 arrested the cell cycle in the G2/M phase and induced apoptosis in PanCa cell lines via modulation of cell cycle regulatory (Cdc2, Cdc25c, and Cyclin B1) and apoptosis - associated (Bax, Bad, Bcl-2, and Bcl-xl) proteins. VERU-111 treatment also inhibited tumor growth (P?

SUBMITTER: Kashyap VK

PROVIDER: S-EPMC6343279 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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Therapeutic efficacy of a novel βIII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer.

Kashyap Vivek K VK Wang Qinghui Q Setua Saini S Nagesh Prashanth K B PKB Chauhan Neeraj N Kumari Sonam S Chowdhury Pallabita P Miller Duane D DD Yallapu Murali M MM Li Wei W Jaggi Meena M Hafeez Bilal Bin BB Chauhan Subhash C SC

Journal of experimental & clinical cancer research : CR 20190123 1

<h4>Background</h4>The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. Among various tubulins, βIII and βIV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not ...[more]

PMID: 30674344

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Project description:Triple-negative breast cancer (TNBC) accounts for approximately 15% of breast cancer cases in the United States. TNBC has poorer overall prognosis relative to other molecular subtypes due to rapid onset of drug resistance to conventional chemotherapies and increased risk of visceral metastases. Taxanes like paclitaxel are standard chemotherapies that stabilize microtubules, but their clinical efficacy is often limited by drug resistance and neurotoxicities. We evaluated the preclinical efficacy of a novel, potent, and orally bioavailable tubulin inhibitor, VERU-111, in TNBC models. VERU-111 showed potent cytotoxicity against TNBC cell lines, inducing apoptosis and cell-cycle arrest in a concentration-dependent manner. VERU-111 also efficiently inhibited colony formation, cell migration, and invasion. Orally administered VERU-111 inhibited MDA-MB-231 xenograft growth in a dose-dependent manner, with similar efficacies to paclitaxel, but without acute toxicity. VERU-111 significantly reduced metastases originating from the mammary fat pad into lung, liver, and kidney metastasis in an experimental metastasis model. Moreover, VERU-111, but not paclitaxel, suppressed growth of luciferase-labeled, taxane-resistant, patient-derived metastatic TNBC tumors. In this model, VERU-111 repressed growth of preestablished axillary lymph node metastases and lung, bone, and liver metastases at study endpoint, whereas paclitaxel enhanced liver metastases relative to vehicle controls. Collectively, these studies strongly suggest that VERU-111 is not only a potent inhibitor of aggressive TNBC phenotypes, but it is also efficacious in a taxane-resistant model of metastatic TNBC. Thus, VERU-111 is a promising new generation of tubulin inhibitor for the treatment of TNBC and may be effective in patients who progress on taxanes.Results presented in this study demonstrate the efficacy of VERU-111 in vivo and provide strong rationale for future development of VERU-111 as an effective treatment for metastatic breast cancer.

Project description:PURPOSE OF REVIEW:Pancreatic cancer is the most devastating of all cancers with an extremely poor prognosis. In US alone, over 50?000 new cases of pancreatic cancer are reported annually, and about the same number succumb to it, making pancreatic cancer the third most common cause of cancer deaths. Most patients with pancreatic cancer present with advanced disease, which cannot be resected surgically, and for these patients chemotherapy is the only option. Even patients who undergo resection require adjuvant therapy to decrease the risk of recurrence. Since the 1950s, a variety of different agents, like antimetabolites, nucleoside analogs, and DNA intercalating compounds, have been used against pancreatic cancer, alone or in combination, with little improvement in the survival statistics. The current article reviews the evolution of chemotherapy for pancreatic cancer, and discusses some novel therapeutic options that are emerging in recent times, with special emphasis on Minnelide, a novel HSP70 inhibitor, which is currently in clinical trials. RECENT FINDINGS:Approaches towards developing therapies for pancreatic cancer have evolved tremendously over the past decade. Research has shown that apart from the inherent drug resistance, drug delivery to pancreatic cancer has also posed a major challenge. The extensive desmoplastic stroma of pancreatic cancer is believed to create inordinately high interstitial fluid pressures leading to vascular collapse and substantial barrier to perfusion of chemotherapeutics, thus creating an additional layer of protection for pancreatic cancer. Recent research thus is focused not only on understanding the biology and developing strategies to target cancer cells, but also is targeted towards the depletion of stroma in order to ensure better delivery of chemotherapeutic compounds to the tumor. SUMMARY:The current article describes the novel therapies that are constantly being evaluated to address and overcome the challenges that make pancreatic cancer a difficult disease to treat.

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Therapeutic efficacy of a novel ?III/?IV-tubulin inhibitor (VERU-111) in pancreatic cancer.

Publications

Therapeutic efficacy of a novel βIII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer.

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