CA : A Cancer Journal for Clinicians

// Reza Bayat Mokhtari 1,2,4 , Tina S. Homayouni 1 , Narges Baluch 3 , Evgeniya Morgatskaya 1 , Sushil Kumar 1 , Bikul Das 4 and Herman Yeger 1,2 1 Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada 2 Department of Paediatric Laboratory Medicine, The Hospital for Sick Children and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada 3 Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada 4 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, Massachusetts, USA Correspondence to: Herman Yeger, email: // Reza Bayat Mokhtari, email: // Keywords : Nrf2-Keap1, HIF-1alpha, carbonic anhydrase 9 (CAIX), histone deacetylase inhibitor (HDACi), carbonic anhydrase inhibitor (CAI) Received : October 19, 2016 Accepted : February 27, 2017 Published : March 30, 2017 Abstract Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner. This approach potentially reduces drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumour growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis. The 5-year survival rates for most metastatic cancers are still quite low, and the process of developing a new anti-cancer drug is costly and extremely time-consuming. Therefore, new strategies that target the survival pathways that provide efficient and effective results at an affordable cost are being considered. One such approach incorporates repurposing therapeutic agents initially used for the treatment of different diseases other than cancer. This approach is effective primarily when the FDA-approved agent targets similar pathways found in cancer. Because one of the drugs used in combination therapy is already FDA-approved, overall costs of combination therapy research are reduced. This increases cost efficiency of therapy, thereby benefiting the “medically underserved”. In addition, an approach that combines repurposed pharmaceutical agents with other therapeutics has shown promising results in mitigating tumour burden. In this systematic review, we discuss important pathways commonly targeted in cancer therapy. Furthermore, we also review important repurposed or primary anti-cancer agents that have gained popularity in clinical trials and research since 2012.

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Combination therapy in combating cancer.

Cancer development is highly associated to the physiological state of the tumor microenvironment (TME). Despite the existing heterogeneity of tumors from the same or from different anatomical locations, common features can be found in the TME maturation of epithelial-derived tumors. Genetic alterations in tumor cells result in hyperplasia, uncontrolled growth, resistance to apoptosis, and metabolic shift towards anaerobic glycolysis (Warburg effect). These events create hypoxia, oxidative stress and acidosis within the TME triggering an adjustment of the extracellular matrix (ECM), a response from neighbor stromal cells (e.g., fibroblasts) and immune cells (lymphocytes and macrophages), inducing angiogenesis and, ultimately, resulting in metastasis. Exosomes secreted by TME cells are central players in all these events. The TME profile is preponderant on prognosis and impacts efficacy of anti-cancer therapies. Hence, a big effort has been made to develop new therapeutic strategies towards a more efficient targeting of TME. These efforts focus on: (i) therapeutic strategies targeting TME components, extending from conventional therapeutics, to combined therapies and nanomedicines; and (ii) the development of models that accurately resemble the TME for bench investigations, including tumor-tissue explants, “tumor on a chip” or multicellular tumor-spheroids.

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Targeting Tumor Microenvironment for Cancer Therapy.

The Food and Drug Administration (FDA) is a regulatory agency of the United States federal government This article describes the scope of work of each of the FDA's major components, and addresses the role of statisticians at FDA


Keywords:

drug regulation;
clinical trials;
medical devices;
safety;
bioassay

Food and Drug Administration (FDA)

Understanding cell-fate decisions during tumorigenesis and metastasis is a major challenge in modern cancer biology. One canonical cell-fate decision that cancer cells undergo is Epithelial-to-Mesenchymal Transition (EMT) and its reverse Mesenchymal-to-Epithelial Transition (MET). While transitioning between these two phenotypes – epithelial and mesenchymal, cells can also attain a hybrid epithelial/ mesenchymal (i.e. partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (eg. adhesion) and mesenchymal (eg. migration) properties, thereby allowing them to move collectively as clusters of Circulating Tumor Cells (CTCs). If these clusters enter the circulation, they can be more apoptosis-resistant and more capable of initiating metastatic lesions than cancer cells moving individually with wholly mesenchymal phenotypes, having undergone a complete EMT. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a ‘three-way’ switch giving rise to three distinct phenotypes – epithelial, mesenchymal and hybrid epithelial/mesenchymal. We further characterize this hybrid E/M phenotype in terms of its capabilities in terms of collective cell migration, tumor-initiation, cell-cell communication, and drug resistance. We elucidate how the highly interconnected coupling between these modules coordinates cell-fate decisions among a population of cancer cells in the dynamic tumor, hence facilitating tumor-stroma interactions, formation of CTC clusters, and consequently cancer metastasis. Finally, we discuss the multiple advantages that the hybrid epithelial/mesenchymal phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary ‘bad actors’ of metastasis.

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Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis

Cancer is a multi-stage process resulting from aberrant signaling pathways driving uncontrolled proliferation of transformed cells. The development and progression of cancer from a premalignant lesion towards a metastatic tumor requires accumulation of mutations in many regulatory genes of the cell. Different chemopreventative approaches have been sought to interfere with initiation and control malignant progression. Here we present research on dietary compounds with evidence of cancer prevention activity that highlights the potential beneficial effect of a diet rich in cruciferous vegetables. The Brassica family of cruciferous vegetables such as broccoli is a rich source of glucosinolates, which are metabolized to isothiocyanate compounds. Amongst a number of related variants of isothiocyanates, sulforaphane (SFN) has surfaced as a particularly potent chemopreventive agent based on its ability to target multiple mechanisms within the cell to control carcinogenesis. Anti-inflammatory, pro-apoptotic and modulation of histones are some of the more important and known mechanisms by which SFN exerts chemoprevention. The effect of SFN on cancer stem cells is another area of interest that has been explored in recent years and may contribute to its chemopreventive properties. In this paper, we briefly review structure, pharmacology and preclinical studies highlighting chemopreventive effects of SFN.

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The role of Sulforaphane in cancer chemoprevention and health benefits: a mini-review

Purpose: Low dose metronomic (LDM) chemotherapy, combined with VEGF signaling pathway inhibitors, is a highly effective strategy to coordinately inhibit angiogenesis and tumor growth in many adult preclinical cancer models. We have tested the efficacies of daily oral LDM topotecan alone and in combination with pazopanib, a VEGF receptor inhibitor, in three pediatric extracranial solid tumor mouse models. Experimental Design: In vitro dose–response study of topotecan and pazopanib was conducted on several neuroblastoma, osteosarcoma, and rhabdomyosarcoma cell lines. In vivo antitumor efficacies of the LDM topotecan and pazopanib as single agents and in combination were tested on 4 subcutaneous xenograft models and on 2 neuroblastoma metastatic models. Circulating angiogenic factors such as circulating endothelial cells (CEC), circulating endothelial pro genitor cells (CEP), and microvessel densities were used as surrogate biomarker markers of antiangiogenic activity. Results: In vitro , topotecan caused a dose-dependent decrease in viabilities of all cell lines, while pazopanib did not. In vivo , combination of topotecan + pazopanib (TP + PZ) showed significant antitumor activity and significant enhancement in survival compared with the respective single agents in all models. Reductions in viable CEP and/or CEC levels and tumor microvessel density were correlated with tumor response and therefore confirmed the antiangiogenic activity of the regimens. Pharmacokinetic studies of both drugs did not reveal any drug–drug interaction. Conclusion: Metronomic administration of TP + PZ showed a statistically significant antitumor activity compared with respective single agents in pediatric tumor mouse models and represent a valid option as a maintenance therapy in aggressive pediatric solid tumors. Clin Cancer Res; 17(17); 5656–67. ©2011 AACR .

https://clincancerres.aacrjournals.org/content/clincanres/17/17/5656.full.pdf

Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor.

Bronchial carcinoids are pulmonary neuroendocrine cell-derived tumors comprising typical (TC) and atypical (AC) malignant phenotypes. The 5-year survival rate in metastatic carcinoid, despite multiple current therapies, is 14-25%. Hence, we are testing novel therapies that can affect the proliferation and survival of bronchial carcinoids. In vitro studies were used for the dose–response (AlamarBlue) effects of acetazolamide (AZ) and sulforaphane (SFN) on clonogenicity, serotonin-induced growth effect and serotonin content (LC-MS) on H-727 (TC) and H-720 (AC) bronchial carcinoid cell lines and their derived NOD/SCID mice subcutaneous xenografts. Tumor ultra structure was studied by electron microscopy. Invasive fraction of the tumors was determined by matrigel invasion assay. Immunohistochemistry was conducted to study the effect of treatment(s) on proliferation (Ki67, phospho histone-H3) and neuroendocrine phenotype (chromogranin-A, tryptophan hydroxylase). Both compounds significantly reduced cell viability and colony formation in a dose-dependent manner (0–80 μM, 48 hours and 7 days) in H-727 and H-720 cell lines. Treatment of H-727 and H-720 subcutaneous xenografts in NOD/SCID mice with the combination of AZ + SFN for two weeks demonstrated highly significant growth inhibition and reduction of 5-HT content and reduced the invasive capacity of H-727 tumor cells. In terms of the tumor ultra structure, a marked reduction in secretory vesicles correlated with the decrease in 5-HT content. The combination of AZ and SFN was more effective than either single agent. Since the effective doses are well within clinical range and bioavailability, our results suggest a potential new therapeutic strategy for the treatment of bronchial carcinoids.

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Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines

Purpose: To investigate the antitumor effect of nab-paclitaxel, an albumin-stabilized nanoparticle formulation of paclitaxel, on pediatric solid tumor models. Experimental Design: A panel of three rhabdomyosarcoma, one osteosarcoma and seven neuroblastoma cell lines were exposed to increasing concentrations of nab-paclitaxel in vitro . Cell viability was evaluated using the Alamar Blue Assay. Antitumor effect was further assessed in vivo in NOD/SCID xenograft and metastatic neuroblastoma mouse models. Tumor sections were analyzed by immunohistochemistry for cleaved caspase-3 and phospho-histone H3. Plasma and intratumoral paclitaxel concentrations were measured by liquid chromatography–mass spectrometry. Ratio of intratumoral and plasma concentration was compared between nab-paclitaxel and paclitaxel treatment groups. Results: Nab-paclitaxel displayed significant cytotoxicity against most pediatric solid tumor cell lines in vitro in a dose-dependent manner. In vivo , nab-paclitaxel showed antitumor activity in both rhabdomyosarcoma (RH4 and RD) and neuroblastoma [SK-N-BE(2) and CHLA-20] xenograft models. In the SK-N-BE(2) metastatic model, nab-paclitaxel treatment significantly extended animal survival compared with control ( P in vivo . In the RH4 model, increased local relapse-free intervals were observed with nab-paclitaxel treatment (37.7 ± 3.2 days) comparing with paclitaxel (13.6 ± 2.07 days). Local relapsed tumors following paclitaxel treatment proved to be paclitaxel-resistant and remained responsive to nab-paclitaxel. Mechanistically, a higher tumor/plasma paclitaxel drug ratio in favor of nab-paclitaxel was observed. Conclusions: Nab-paclitaxel showed significant antitumor activity against all pediatric solid tumors associated with an enhanced drug intratumor delivery. Furthermore, testing of nab-paclitaxel in pediatric solid-tumor patient population is under development. Clin Cancer Res; 19(21); 5972–83. ©2013 AACR .

https://clincancerres.aacrjournals.org/content/clincanres/19/21/5972.full.pdf

Sushil Kumar

Papers

Combination therapy in combating cancer.

The role of Sulforaphane in cancer chemoprevention and health benefits: a mini-review

Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor.

Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines

Nab-Paclitaxel Is an Active Drug in Preclinical Model of Pediatric Solid Tumors