Expert Opinion on Therapeutic Targets
ISSN: 1472-8222 (Print) 1744-7631 (Online) Journal homepage: http://www.tandfonline.com/loi/iett20
Head and neck cancers, the neglected malignancies: present and future treatment strategies Pushkar Kulkarni MVM & Uday Saxena PhD To cite this article: Pushkar Kulkarni MVM & Uday Saxena PhD (2014) Head and neck cancers, the neglected malignancies: present and future treatment strategies, Expert Opinion on Therapeutic Targets, 18:4, 351-354 To link to this article: http://dx.doi.org/10.1517/14728222.2014.888059
Published online: 10 Feb 2014.
Submit your article to this journal
Article views: 227
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iett20 Download by: [Penn State University]
Date: 15 November 2015, At: 06:44
Editorial
1.
Introduction
2.
Presently approved therapies
3.
Suggested targeted approaches for the future
Downloaded by [Penn State University] at 06:44 15 November 2015
4.
Head and neck cancers, the neglected malignancies: present and future treatment strategies Pushkar Kulkarni & Uday Saxena† †
Kareus Therapeutics, La Chaux-de-Fonds, Switzerland
Expert opinion
Head and neck cancers are the most prevalent cancers in Asia and result in 50% of deaths due to all cancers in that region. However, treatment regimen has not changed in the past two decades and there are no specific drugs for this cancer. As a result of this, treatment outcomes remain poor. Furthermore, there are no new breakthrough therapies on the horizon, in part, due to low commercial interest in these cancers. What is needed is new thinking, which combines targeted and risk mitigation approaches to develop novel drugs. This editorial will focus on summarising the present approaches to treatment and propose new targets for these cancers. Keywords: adenosine monophosphate-activated protein kinase, cytotoxic chemotherapeutic drugs, head and neck cancer, peroxisomal proliferator activated receptor g, phosphodiesterase 4, target-based therapy Expert Opin. Ther. Targets (2014) 18(4):351-354
1.
Introduction
Head and neck cancers are the most prevalent amongst all cancers in male populations in developing Asian countries such as India and China [1]. Some of the reasons attributed to this prevalence are related to use of smokeless chewing tobacco, alcoholism, occupational exposure to carcinogens and human papillomavirus [2]. In poorer nations, occupational exposure-related head and neck cancers are common in construction workers and other types of industrial labour owing to sub-standard occupational safety practices. The traditional approach to treatment of head and neck cancers is the use of general cytotoxic agents. There are two issues with the use of non-targeted, non-specific cytotoxic agents: i) because they are not necessarily designed to target pathways involved in genesis of head and neck cancer, they are less effective; and ii) because they are cytotoxic to both cancer and normal cells they have side effects such as inflammation of oral cavities, convulsions and even cognitive dysfunction. The prevalence of these cancers in poor and underprivileged populations is much higher as compared to the total population. Moreover, surgical treatments are inaccessible and unaffordable to such populations. Therefore, better chemotherapeutic approaches will not only meet an unmet need but also have a major societal impact. We propose a ‘repositioning’ of existing targets/ drugs for head/neck cancers as a way to accelerate bringing new therapies to the market for such cancers. 2.
Presently approved therapies
The US FDA-approved drugs for head and neck cancers, that is, in the nasal cavity, sinuses, lips, mouth, salivary glands, throat and larynx are shown in Table 1 [2]. As shown in Table 1, most of these cytotoxic drugs have side effects related to head 10.1517/14728222.2014.888059 © 2014 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631 All rights reserved: reproduction in whole or in part not permitted
351
P. Kulkarni & U. Saxena
Table 1. List of drugs approved by FDA [2] for head and neck cancers, with their target/mechanism of action, efficacy and safety issues relevant to head and neck cancers. Drug (generic name)
Target/mechanism of action
Efficacy for head and neck cancers
Safety issues relevant to head and neck cancers
Methotrexate Fluorouracil Bleomycin Cetuximab
Inhibition of dihydrofolate reductase Inhibition of thymidylate synthase Inhibition of DNA synthesis Epidermal growth factor receptor inhibitor Alkylating agent Preventing microtubule depolymerisation
Low Low Low Moderate
Ulcerative stomatistis, cognitive effects Mucositis, dermatitis, CNS degeneration Dermatographism, hyperpigmentation Dizzines, anaphylactic shock
Moderate Low
Neurotoxicity, ototoxicity Effect on neurosensory and neuromotor response
Downloaded by [Penn State University] at 06:44 15 November 2015
Cisplatin Docetaxel
and neck anatomy. A second observation is that their efficacy for head and neck cancers is low (response rate < 10%) to moderate (response rate > 10% but < 50%). 3. Suggested targeted approaches for the future
Here we propose three targeted approaches for treatment of head and neck. Design and use of drugs that target specific proteins, enzymes or genes are more likely to have a better efficacy/safety profile rather than general cytotoxic agents. Although the targets we suggest do have some preclinical validation, they do not have clinical verification supporting their role in head and neck cancers. But these targets are well studied and have approved drugs targeting them for other disease indications, which will enable their rapid testing for efficacy in human head and neck cancers. Phosphodiesterase 4 Phosphodiesterases (PDEs) are a family of enzymes that degrade cAMP and therefore control the intracellular concentration of this second messenger. Because of their distinct tissue distribution and regulation among various cell types, PDEs are the most important regulators of intracellular cAMP levels and connected signal transduction pathways [3]. PDE4 belongs to this family of enzymes and has been proposed to have a role in growth and tumour promotion. Low levels of cAMP are correlated with greater malignancy. Consistent with this, studies indicate that high concentrations of cAMP inhibit the growth of many cell types, including cells derived from brain tumours [4]. Indeed, addition of cyclic AMP or use of compounds that increase its intracellular concentration, for example, PDE inhibitors, decreases cellular growth. A specific PDE4 inhibitor, roflumilast, has recently been approved and marketed for treatment of severe chronic obstructive pulmonary disease, demonstrating its efficacy and safety in humans [5]. This drug has been shown in preclinical studies to have an efficacious effect against a variety of tumours [6,7]. Roflumilast may be an ideal drug to test in head and neck cancers in proof-of-concept human clinical studies. 3.1
352
Adenosine monophosphate-activated protein kinase
3.2
Adenosine monophosphate-activated protein kinase (AMPK) enzyme acts as an antenna of cellular energy status in all mammalian cells. It is activated by increases in the intracellular AMP:ATP ratio, which is changed by energy consumption or production. Its activation involves phosphorylation by tumour suppressor LKB1, an upstream kinase [8]. After activation, AMPK turns on bio-energetic pathways that generate ATP, while switching off ATP-consuming processes like cell growth and proliferation. Thus, AMPK activation leads to growth inhibitory effects. In support of this, preclinical studies show that an AMPK activator called metformin exerts antitumour effects in numerous human cancer cells [9-14]. Metformin is a successful and well-established drug for treatment of type 2 diabetes and therefore can be easily tested in clinical trials for head and neck cancers. Peroxisomal proliferator-activated receptor g Peroxisomal proliferator-activated receptor g (PPARg) belongs to a family of established nuclear hormone receptors that regulate transcription of target genes. The critical regulatory role of PPARg in insulin sensitisation and lipid metabolism is well documented. As a link to cancer, studies show that it is over-expressed in several human cancer cells [15,16]. Furthermore, PPARg activation by specific agonists leads to inhibition of growth, apoptosis and differentiation in tumour cells [17]. Pharmacologic PPARg activators called thiazolidinediones (pioglitazone and rosiglitazone) have been approved and marketed for treatment of type 2 diabetes. In preclinical studies the effect of PPARg activators in cancer cells has been well studied and found to be effective [18-20]. These drugs could be used in clinical trials to test whether modulation of PPARg can result in effective treatment of head and neck cancers. 3.3
4.
Expert opinion
Because of lower incidence of head and neck cancers in the western world, there is less interest from big pharma
Expert Opin. Ther. Targets (2014) 18(4)
Downloaded by [Penn State University] at 06:44 15 November 2015
Head and neck cancers, the neglected malignancies: present and future treatment strategies
companies in developing new drugs for these cancers. As a result of this, there are no new therapies in the pipeline and these cancers can be viewed as ‘neglected diseases’. As such, there is an urgent unmet need to develop new targeted therapies for such cancers. What is required for the next generation drugs is to specifically attack molecular targets involved in disease-causing pathways. Preclinical discovery and validation of new targets can take a long time as well as be an expensive proposition. The clinical development of an efficacious and safe drug takes even longer and the expenses involved for human trails are log order more than preclinical research. One way to accelerate this process for such neglected diseases is to use existing targets that are disease causing in head and neck and marry the target to an existing drug even if it is for an unrelated indication. By doing so one would rely on the known safety of the drug, and since 50% of all drugs fail due to safety reasons, the risk and costs of development will be markedly reduced. Here we propose three targets with Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
American Cancer Society. Global cancer facts & figures. 2nd edition. American Cancer Society, Atlanta; 2011
2.
Drugs Approved for Head and Neck Cancer. Cancer Drug Information, National Cancer Institute at the National Institute of Health. Available from: http://www.cancer.gov/cancertopics/ druginfo/head-and-neck-cancer [Last accessed 11 December 2013]
3.
.
4.
5.
6.
Lerner A, Kim DH, Lee R. The cAMP signaling pathway as a therapeutic target in lymphoid malignancies. Leuk Lymphoma 2000;37(1-2):39-51 Good resource for understanding role cAMP pathway in cancer. Goldhoff P, Warrington NM, Limbrick DD Jr, et al. Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression. Clin Cancer Res 2008;14(23):7717-25 Lipari M, Benipal H, Kale-Pradhan P. Roflumilast in the management of chronic obstructive pulmonary disease. Am J Health Syst Pharm 2013;70(23):2087-95 Moon E, Lee R, Near R, et al. Inhibition of PDE3B augments PDE4 inhibitorinduced apoptosis in a subset of patients with chronic lymphocytic leukemia. Clin Cancer Res 2002;8(2):589-95
7.
8.
.
9.
preclinical potential to be useful in head and neck cancers. Each of the proposed targets has an existing marketed drug, which can then be tested in clinical trials for head and neck cancers. Another attractive feature of these drugs is that they can be used in combination with the existing cytotoxic drugs currently in use. It is our belief that this approach of testing known drugs against new targets will leapfrog the process of bringing new drugs to the patients for these neglected cancers.
Acknowledgement U Saxena would like to dedicate this paper in memory of his mentors Sailen Mookerjea and K Anji Reddy.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.
Chen TC, Wadsten P, Su S, et al. The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cip1) and p27 (Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells. Cancer Biol Ther 2002;1(3):268-76 Shackelford DB, Shaw RJ. The LKB1AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 2009;9(8):563-75 Excellent overview of AMPK pathway’s role in cancer. Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia 2013;56(9):1898-906
10.
Luo Q, Hu D, Hu S, et al. In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma. BMC Cancer 2012;12:517
11.
Sandulache VC, Hamblin JS, Skinner HD, et al. Metformin use is associated with improved survival in patients with laryngeal squamous cell carcinoma. Head Neck 2013, doi:10.1002/hed.23409
12.
Vitale-Cross L, Molinolo AA, Martin D, et al. Metformin prevents the development of oral squamous cell carcinomas from carcinogen-induced premalignant lesions. Cancer Prev Res (Phila) 2012;5(4):562-73
Expert Opin. Ther. Targets (2014) 18(4)
13.
Sikka A, Kaur M, Agarwal C, et al. Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation. Cell Cycle 2012;11(7):1374-82
14.
Zhao L, Wen ZH, Jia CH, et al. Metformin induces G1 cell cycle arrest and inhibits cell proliferation in nasopharyngeal carcinoma cells. Anat Rec (Hoboken) 2011;294(8):1337-43
15.
Ahmadian M, Suh JM, Hah N, et al. PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med 2013;19(5):557-66 Good review of the various biological roles of PPARg.
.
16.
Krishnan A, Nair SA, Pillai MR. Biology of PPAR gamma in cancer: a critical review on existing lacunae. Curr Mol Med 2007;7(6):532-40
17.
Panigrahy D, Huang S, Kieran MW, Kaipainen A. PPARgamma as a therapeutic target for tumor angiogenesis and metastasis. Cancer Biol Ther 2005;4(7):687-93
18.
Nakashiro K, Begum NM, Uchida D, et al. Thiazolidinediones inhibit cell growth of human oral squamous cell carcinoma in vitro independent of peroxisome proliferator-activated receptor gamma. Oral Oncol 2003;39(8):855-61
19.
Rumi MA, Sato H, Ishihara S, et al. Growth inhibition of esophageal squamous carcinoma cells by peroxisome
353
P. Kulkarni & U. Saxena
proliferator-activated receptor-gamma ligands. J Lab Clin Med 2002;140(1):17-26 20.
Begum NM, Nakashiro K, Kawamata H, et al. Expression of peroxisome proliferator-activated receptor gamma and the growth inhibitory effect of its synthetic ligands in human salivary gland cancer cell lines. Int J Oncol 2002;20(3):599-605
Downloaded by [Penn State University] at 06:44 15 November 2015
Affiliation
Pushkar Kulkarni1 MVM & Uday Saxena†2 PhD † Author for correspondence 1 University of Hyderabad Campus, Dr. Reddy’s Institute of Life Sciences, Gachibowli, Hyderabad, India 2 Kareus Therapeutics, SA. 40 Rue Fritz-Courvoisier, 2300 La Chaux-de-Fonds, Switzerland Tel: +41 32 967 9024; Fax: +41 32 967 95 96; E-mail: [email protected]
354
Expert Opin. Ther. Targets (2014) 18(4)
ISSN: 1472-8222 (Print) 1744-7631 (Online) Journal homepage: http://www.tandfonline.com/loi/iett20
Head and neck cancers, the neglected malignancies: present and future treatment strategies Pushkar Kulkarni MVM & Uday Saxena PhD To cite this article: Pushkar Kulkarni MVM & Uday Saxena PhD (2014) Head and neck cancers, the neglected malignancies: present and future treatment strategies, Expert Opinion on Therapeutic Targets, 18:4, 351-354 To link to this article: http://dx.doi.org/10.1517/14728222.2014.888059
Published online: 10 Feb 2014.
Submit your article to this journal
Article views: 227
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iett20 Download by: [Penn State University]
Date: 15 November 2015, At: 06:44
Editorial
1.
Introduction
2.
Presently approved therapies
3.
Suggested targeted approaches for the future
Downloaded by [Penn State University] at 06:44 15 November 2015
4.
Head and neck cancers, the neglected malignancies: present and future treatment strategies Pushkar Kulkarni & Uday Saxena† †
Kareus Therapeutics, La Chaux-de-Fonds, Switzerland
Expert opinion
Head and neck cancers are the most prevalent cancers in Asia and result in 50% of deaths due to all cancers in that region. However, treatment regimen has not changed in the past two decades and there are no specific drugs for this cancer. As a result of this, treatment outcomes remain poor. Furthermore, there are no new breakthrough therapies on the horizon, in part, due to low commercial interest in these cancers. What is needed is new thinking, which combines targeted and risk mitigation approaches to develop novel drugs. This editorial will focus on summarising the present approaches to treatment and propose new targets for these cancers. Keywords: adenosine monophosphate-activated protein kinase, cytotoxic chemotherapeutic drugs, head and neck cancer, peroxisomal proliferator activated receptor g, phosphodiesterase 4, target-based therapy Expert Opin. Ther. Targets (2014) 18(4):351-354
1.
Introduction
Head and neck cancers are the most prevalent amongst all cancers in male populations in developing Asian countries such as India and China [1]. Some of the reasons attributed to this prevalence are related to use of smokeless chewing tobacco, alcoholism, occupational exposure to carcinogens and human papillomavirus [2]. In poorer nations, occupational exposure-related head and neck cancers are common in construction workers and other types of industrial labour owing to sub-standard occupational safety practices. The traditional approach to treatment of head and neck cancers is the use of general cytotoxic agents. There are two issues with the use of non-targeted, non-specific cytotoxic agents: i) because they are not necessarily designed to target pathways involved in genesis of head and neck cancer, they are less effective; and ii) because they are cytotoxic to both cancer and normal cells they have side effects such as inflammation of oral cavities, convulsions and even cognitive dysfunction. The prevalence of these cancers in poor and underprivileged populations is much higher as compared to the total population. Moreover, surgical treatments are inaccessible and unaffordable to such populations. Therefore, better chemotherapeutic approaches will not only meet an unmet need but also have a major societal impact. We propose a ‘repositioning’ of existing targets/ drugs for head/neck cancers as a way to accelerate bringing new therapies to the market for such cancers. 2.
Presently approved therapies
The US FDA-approved drugs for head and neck cancers, that is, in the nasal cavity, sinuses, lips, mouth, salivary glands, throat and larynx are shown in Table 1 [2]. As shown in Table 1, most of these cytotoxic drugs have side effects related to head 10.1517/14728222.2014.888059 © 2014 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631 All rights reserved: reproduction in whole or in part not permitted
351
P. Kulkarni & U. Saxena
Table 1. List of drugs approved by FDA [2] for head and neck cancers, with their target/mechanism of action, efficacy and safety issues relevant to head and neck cancers. Drug (generic name)
Target/mechanism of action
Efficacy for head and neck cancers
Safety issues relevant to head and neck cancers
Methotrexate Fluorouracil Bleomycin Cetuximab
Inhibition of dihydrofolate reductase Inhibition of thymidylate synthase Inhibition of DNA synthesis Epidermal growth factor receptor inhibitor Alkylating agent Preventing microtubule depolymerisation
Low Low Low Moderate
Ulcerative stomatistis, cognitive effects Mucositis, dermatitis, CNS degeneration Dermatographism, hyperpigmentation Dizzines, anaphylactic shock
Moderate Low
Neurotoxicity, ototoxicity Effect on neurosensory and neuromotor response
Downloaded by [Penn State University] at 06:44 15 November 2015
Cisplatin Docetaxel
and neck anatomy. A second observation is that their efficacy for head and neck cancers is low (response rate < 10%) to moderate (response rate > 10% but < 50%). 3. Suggested targeted approaches for the future
Here we propose three targeted approaches for treatment of head and neck. Design and use of drugs that target specific proteins, enzymes or genes are more likely to have a better efficacy/safety profile rather than general cytotoxic agents. Although the targets we suggest do have some preclinical validation, they do not have clinical verification supporting their role in head and neck cancers. But these targets are well studied and have approved drugs targeting them for other disease indications, which will enable their rapid testing for efficacy in human head and neck cancers. Phosphodiesterase 4 Phosphodiesterases (PDEs) are a family of enzymes that degrade cAMP and therefore control the intracellular concentration of this second messenger. Because of their distinct tissue distribution and regulation among various cell types, PDEs are the most important regulators of intracellular cAMP levels and connected signal transduction pathways [3]. PDE4 belongs to this family of enzymes and has been proposed to have a role in growth and tumour promotion. Low levels of cAMP are correlated with greater malignancy. Consistent with this, studies indicate that high concentrations of cAMP inhibit the growth of many cell types, including cells derived from brain tumours [4]. Indeed, addition of cyclic AMP or use of compounds that increase its intracellular concentration, for example, PDE inhibitors, decreases cellular growth. A specific PDE4 inhibitor, roflumilast, has recently been approved and marketed for treatment of severe chronic obstructive pulmonary disease, demonstrating its efficacy and safety in humans [5]. This drug has been shown in preclinical studies to have an efficacious effect against a variety of tumours [6,7]. Roflumilast may be an ideal drug to test in head and neck cancers in proof-of-concept human clinical studies. 3.1
352
Adenosine monophosphate-activated protein kinase
3.2
Adenosine monophosphate-activated protein kinase (AMPK) enzyme acts as an antenna of cellular energy status in all mammalian cells. It is activated by increases in the intracellular AMP:ATP ratio, which is changed by energy consumption or production. Its activation involves phosphorylation by tumour suppressor LKB1, an upstream kinase [8]. After activation, AMPK turns on bio-energetic pathways that generate ATP, while switching off ATP-consuming processes like cell growth and proliferation. Thus, AMPK activation leads to growth inhibitory effects. In support of this, preclinical studies show that an AMPK activator called metformin exerts antitumour effects in numerous human cancer cells [9-14]. Metformin is a successful and well-established drug for treatment of type 2 diabetes and therefore can be easily tested in clinical trials for head and neck cancers. Peroxisomal proliferator-activated receptor g Peroxisomal proliferator-activated receptor g (PPARg) belongs to a family of established nuclear hormone receptors that regulate transcription of target genes. The critical regulatory role of PPARg in insulin sensitisation and lipid metabolism is well documented. As a link to cancer, studies show that it is over-expressed in several human cancer cells [15,16]. Furthermore, PPARg activation by specific agonists leads to inhibition of growth, apoptosis and differentiation in tumour cells [17]. Pharmacologic PPARg activators called thiazolidinediones (pioglitazone and rosiglitazone) have been approved and marketed for treatment of type 2 diabetes. In preclinical studies the effect of PPARg activators in cancer cells has been well studied and found to be effective [18-20]. These drugs could be used in clinical trials to test whether modulation of PPARg can result in effective treatment of head and neck cancers. 3.3
4.
Expert opinion
Because of lower incidence of head and neck cancers in the western world, there is less interest from big pharma
Expert Opin. Ther. Targets (2014) 18(4)
Downloaded by [Penn State University] at 06:44 15 November 2015
Head and neck cancers, the neglected malignancies: present and future treatment strategies
companies in developing new drugs for these cancers. As a result of this, there are no new therapies in the pipeline and these cancers can be viewed as ‘neglected diseases’. As such, there is an urgent unmet need to develop new targeted therapies for such cancers. What is required for the next generation drugs is to specifically attack molecular targets involved in disease-causing pathways. Preclinical discovery and validation of new targets can take a long time as well as be an expensive proposition. The clinical development of an efficacious and safe drug takes even longer and the expenses involved for human trails are log order more than preclinical research. One way to accelerate this process for such neglected diseases is to use existing targets that are disease causing in head and neck and marry the target to an existing drug even if it is for an unrelated indication. By doing so one would rely on the known safety of the drug, and since 50% of all drugs fail due to safety reasons, the risk and costs of development will be markedly reduced. Here we propose three targets with Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
American Cancer Society. Global cancer facts & figures. 2nd edition. American Cancer Society, Atlanta; 2011
2.
Drugs Approved for Head and Neck Cancer. Cancer Drug Information, National Cancer Institute at the National Institute of Health. Available from: http://www.cancer.gov/cancertopics/ druginfo/head-and-neck-cancer [Last accessed 11 December 2013]
3.
.
4.
5.
6.
Lerner A, Kim DH, Lee R. The cAMP signaling pathway as a therapeutic target in lymphoid malignancies. Leuk Lymphoma 2000;37(1-2):39-51 Good resource for understanding role cAMP pathway in cancer. Goldhoff P, Warrington NM, Limbrick DD Jr, et al. Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression. Clin Cancer Res 2008;14(23):7717-25 Lipari M, Benipal H, Kale-Pradhan P. Roflumilast in the management of chronic obstructive pulmonary disease. Am J Health Syst Pharm 2013;70(23):2087-95 Moon E, Lee R, Near R, et al. Inhibition of PDE3B augments PDE4 inhibitorinduced apoptosis in a subset of patients with chronic lymphocytic leukemia. Clin Cancer Res 2002;8(2):589-95
7.
8.
.
9.
preclinical potential to be useful in head and neck cancers. Each of the proposed targets has an existing marketed drug, which can then be tested in clinical trials for head and neck cancers. Another attractive feature of these drugs is that they can be used in combination with the existing cytotoxic drugs currently in use. It is our belief that this approach of testing known drugs against new targets will leapfrog the process of bringing new drugs to the patients for these neglected cancers.
Acknowledgement U Saxena would like to dedicate this paper in memory of his mentors Sailen Mookerjea and K Anji Reddy.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.
Chen TC, Wadsten P, Su S, et al. The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cip1) and p27 (Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells. Cancer Biol Ther 2002;1(3):268-76 Shackelford DB, Shaw RJ. The LKB1AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 2009;9(8):563-75 Excellent overview of AMPK pathway’s role in cancer. Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia 2013;56(9):1898-906
10.
Luo Q, Hu D, Hu S, et al. In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma. BMC Cancer 2012;12:517
11.
Sandulache VC, Hamblin JS, Skinner HD, et al. Metformin use is associated with improved survival in patients with laryngeal squamous cell carcinoma. Head Neck 2013, doi:10.1002/hed.23409
12.
Vitale-Cross L, Molinolo AA, Martin D, et al. Metformin prevents the development of oral squamous cell carcinomas from carcinogen-induced premalignant lesions. Cancer Prev Res (Phila) 2012;5(4):562-73
Expert Opin. Ther. Targets (2014) 18(4)
13.
Sikka A, Kaur M, Agarwal C, et al. Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation. Cell Cycle 2012;11(7):1374-82
14.
Zhao L, Wen ZH, Jia CH, et al. Metformin induces G1 cell cycle arrest and inhibits cell proliferation in nasopharyngeal carcinoma cells. Anat Rec (Hoboken) 2011;294(8):1337-43
15.
Ahmadian M, Suh JM, Hah N, et al. PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med 2013;19(5):557-66 Good review of the various biological roles of PPARg.
.
16.
Krishnan A, Nair SA, Pillai MR. Biology of PPAR gamma in cancer: a critical review on existing lacunae. Curr Mol Med 2007;7(6):532-40
17.
Panigrahy D, Huang S, Kieran MW, Kaipainen A. PPARgamma as a therapeutic target for tumor angiogenesis and metastasis. Cancer Biol Ther 2005;4(7):687-93
18.
Nakashiro K, Begum NM, Uchida D, et al. Thiazolidinediones inhibit cell growth of human oral squamous cell carcinoma in vitro independent of peroxisome proliferator-activated receptor gamma. Oral Oncol 2003;39(8):855-61
19.
Rumi MA, Sato H, Ishihara S, et al. Growth inhibition of esophageal squamous carcinoma cells by peroxisome
353
P. Kulkarni & U. Saxena
proliferator-activated receptor-gamma ligands. J Lab Clin Med 2002;140(1):17-26 20.
Begum NM, Nakashiro K, Kawamata H, et al. Expression of peroxisome proliferator-activated receptor gamma and the growth inhibitory effect of its synthetic ligands in human salivary gland cancer cell lines. Int J Oncol 2002;20(3):599-605
Downloaded by [Penn State University] at 06:44 15 November 2015
Affiliation
Pushkar Kulkarni1 MVM & Uday Saxena†2 PhD † Author for correspondence 1 University of Hyderabad Campus, Dr. Reddy’s Institute of Life Sciences, Gachibowli, Hyderabad, India 2 Kareus Therapeutics, SA. 40 Rue Fritz-Courvoisier, 2300 La Chaux-de-Fonds, Switzerland Tel: +41 32 967 9024; Fax: +41 32 967 95 96; E-mail: [email protected]
354
Expert Opin. Ther. Targets (2014) 18(4)
