Current Drug Targets (v.15, #1)

Targeting Tumor Suppressor Networks for Cancer Therapeutics by Xuning Emily Guo, Bryan Ngo, Aram Sandaldjian Modrek, Wen-Hwa Lee (2-16).
Cancer is a consequence of mutations in genes that control cell proliferation, differentiation and cellular homeostasis.These genes are classified into two categories: oncogenes and tumor suppressor genes. Together, overexpressionof oncogenes and loss of tumor suppressors are the dominant driving forces for tumorigenesis. Hence, targeting oncogenesand tumor suppressors hold tremendous therapeutic potential for cancer treatment. In the last decade, the predominantcancer drug discovery strategy has relied on a traditional reductionist approach of dissecting molecular signalingpathways and designing inhibitors for the selected oncogenic targets. Remarkable therapies have been developed usingthis approach; however, targeting oncogenes is only part of the picture. Our understanding of the importance of tumorsuppressors in preventing tumorigenesis has also advanced significantly and provides a new therapeutic window of opportunity.Given that tumor suppressors are frequently mutated, deleted, or silenced with loss-of-function, restoring theirnormal functions to treat cancer holds tremendous therapeutic potential. With the rapid expansion in our knowledge ofcancer over the last several decades, developing effective anticancer regimens against tumor suppressor pathways hasnever been more promising. In this article, we will review the concept of tumor suppression, and outline the major therapeuticstrategies and challenges of targeting tumor suppressor networks for cancer therapeutics.

Targeting the BRCA1/2 Tumor Suppressors by Eliot M. Rosen, Michael J. Pishvaian (17-31).
The breast cancer susceptibility genes BRCA1 and BRCA2 are classic tumor suppressor genes that exhibit anautosomal dominant pattern of inheritance with high penetrance. BRCA carriers inherit one mutant BRCA allele and onewild-type allele; and the wild-type allele is invariably deleted or mutated within the tumor. These genes function as caretakersin the maintenance of genomic stability, in part, by participating in homology-directed DNA repair (HDR), an error-free mechanism for the repair of double-strand breaks (DSBs). PARP1 (poly (ADP-ribose) polymerase 1) is an enzymethat functions in the base excision repair (BER) pathway, where its ability to post-translationally modify histonesand DNA damage response proteins is required for repair of single-strand breaks (SSBs). In 2005, it was observed thatknockdown of PARP1 or treatment with a small molecule PARP inhibitor was far more toxic to cells with BRCA1 orBRCA2 mutations than BRCA1/2-competent cells. This observation is an example of “synthetic lethality”, a conceptwhereby two gene mutations combine to cause cell death, when neither mutation alone is lethal. These results spawned theidea to use PARP inhibitors to treat BRCA1/2 mutant cancers. Here, we will review the basic science underlying the discoveriesdescribed above, the preclinical research, and the clinical trials designed to exploit the sensitivity of BRCA1/2mutant tumor cells to PARP inhibitors. We will also describe problems associated with the use of these agents, includingdevelopment and mechanisms of drug resistance; and we will provide a forward look at new agents and strategies currentlyunder development.

Targeting the LKB1 Tumor Suppressor by Rui-Xun Zhao, Zhi-Xiang Xu (32-52).
LKB1 (also known as serine-threonine kinase 11, STK11) is a tumor suppressor, which is mutated or deleted inPeutz-Jeghers syndrome (PJS) and in a variety of cancers. Physiologically, LKB1 possesses multiple cellular functions inthe regulation of cell bioenergetics metabolism, cell cycle arrest, embryo development, cell polarity, and apoptosis. Newstudies demonstrated that LKB1 may also play a role in the maintenance of function and dynamics of hematopoietic stemcells. Over the past years, personalized therapy targeting specific genetic aberrations has attracted intense interests. Withinthis review, several agents with potential activity against aberrant LKB1 signaling have been discussed. Potential strategiesand challenges in targeting LKB1 inactivation are also considered.

Translating Mismatch Repair Mechanism into Cancer Care by Christopher D. Heinen (53-64).
The first DNA mismatch repair gene was identified in Escherichia coli nearly fifty years ago. Since then, fivedecades of basic biomedical research on this important repair pathway have led to an extensive understanding of its molecularmechanism. The significance of this work was clearly highlighted in the early 1990's when mutations in the humanhomologs of the mismatch repair genes were identified as responsible for Lynch syndrome (also known as hereditarynon-polyposis colon cancer), the most common form of hereditary colorectal cancer. Basic science research on mismatchrepair in lower organisms directly led researchers to the discovery of this link between defective mismatch repair and cancerand continues to guide clinical decisions today. The knowledge that disrupted mismatch repair function gives rise tothe nucleotide-level form of genomic instability called microsatellite instability continues to be an important diagnostictool for identifying Lynch syndrome patients as well as sporadic cancer patients who suffer from mismatch repairdefectivecancers. Today, clinicians are using the information about mismatch repair molecular mechanism to guide decisionsabout cancer therapy as well to devise new therapies. In this review, we will examine what is known about the molecularfunction of the human mismatch repair pathway. We will highlight how this information is being used in cancerdiagnosis and treatment. We will also discuss strategies being designed to target the 10-15% of colorectal, endometrial,ovarian and other cancers with defective mismatch repair.

Therapeutic Targeting of Cancers with Loss of PTEN Function by Lloye M. Dillon, Todd W. Miller (65-79).
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is one of the most frequently disruptedtumor suppressors in cancer. The lipid phosphatase activity of PTEN antagonizes the phosphatidylinositol 3-kinase(PI3K)/AKT/mTOR pathway to repress tumor cell growth and survival. In the nucleus, PTEN promotes chromosome stabilityand DNA repair. Consequently, loss of PTEN function increases genomic instability. PTEN deficiency is caused byinherited germline mutations, somatic mutations, epigenetic and transcriptional silencing, post-translational modifications,and protein-protein interactions. Given the high frequency of PTEN deficiency across cancer subtypes, therapeutic approachesthat exploit PTEN loss-of-function could provide effective treatment strategies. Herein, we discuss therapeuticstrategies aimed at cancers with loss of PTEN function, and the challenges involved in treating patients afflicted with suchcancers. We review preclinical and clinical findings, and highlight novel strategies under development to target PTENdeficientcancers.

Targeting Tumor Suppressor p53 for Cancer Therapy: Strategies, Challenges and Opportunities by Bo Hong, A. Pieter J. van den Heuvel, Varun V. Prabhu, Shengliang Zhang, Wafik S. El-Deiry (80-89).
p53 is one of the most important tumor suppressor genes that is frequently mutated in human cancers. Generally,p53 functions as a transcription factor that is stabilized and activated by various genotoxic and cellular stress signals,such as DNA damage, hypoxia, oncogene activation and nutrient deprivation, consequently leading to cell cycle arrest,apoptosis, senescence and metabolic adaptation. p53 not only becomes functionally deficient in most cancers, but not infrequentlymutant p53 also acquires dominant negative activity and oncogenic properties. p53 has remained an attractivetarget for cancer therapy. Strategies targeting p53 have been developed including gene therapy to restore p53 function, inhibitionof p53-MDM2 interaction, restoration of mutant p53 to wild-type p53, targeting p53 family proteins, eliminatingmutant p53, as well as p53-based vaccines. Some of these p53-targeted therapies have entered clinical trials. We discussthe therapeutic potential of p53, with particular focus on the therapeutic strategies to rescue p53 inactivation in humancancers. In addition, we discuss the challenges of p53-targeted therapy and new opportunities for the future.

Exploiting APC Function as a Novel Cancer Therapy by Alyssa C. Lesko, Kathleen H. Goss, Jenifer R. Prosperi (90-102).
The Adenomatous Polyposis Coli (APC) tumor suppressor is most commonly mutated in colorectal cancerssuch as familial adenomatous polyposis (FAP); as well as many other epithelial cancers like breast, pancreatic, and lungcancer. APC mutations usually result in a truncated form of the protein lacking the carboxy-terminal region resulting inloss of function. Mutations in APC have been identified in early stages of cancer development making it a gatekeeper oftumor progression and therefore an ideal therapeutic target. APC is best known for its role as a negative regulator of theWnt/β -catenin pathway. However, APC also mediates several other normal cell functions independently of Wnt/β-cateninsignaling such as apical-basal polarity, microtubule networks, cell cycle, DNA replication and repair, apoptosis, and cellmigration. Given the vast cellular processes involving APC, the loss of these “normal” functions due to mutation can contributeto chemotherapeutic resistance. Several therapeutic treatments have been explored to restore APC function includingthe reintroduction of APC into mutant cells, inhibiting pathways activated by the loss of APC, and targeting APCmutantcells for apoptosis. This review will discuss the normal functions of APC as they relate to potential treatments forpatients, the role of APC loss in several types of epithelial cancers, and an overview of therapeutic options targeting boththe Wnt-dependent and -independent functions of APC.

The RNA-Dependent-RNA Polymerase, an Emerging Antiviral Drug Target for the Hendra Virus by Tony Velkov, Vincenzo Carbone, Jesmin Akter, Sivashangarie Sivanesan, Jian Li, Travis Beddoe, Glenn A. Marsh (103-113).
Australia is facing a major national medical challenge with the emergence of the Hendra virus (HeV) as amedically and economically important pathogen of humans and animals. Clinical symptoms of human HeV infection caninclude fever, hypotension, dizziness, encephalitis, respiratory haemorrhage and edema. The window of opportunity forsuccessful patient treatment remains unknown, but is likely to be very narrow. Currently, very few effective therapeuticoptions are available for the case management of severe HeV infections or the rapid silencing of local outbreaks. This underscoresthe need for more activity in the drug discovery arena to develop much needed therapeutics that specifically targetsthis deadly disease. The structural analysis of HeV is very much in its infancy, which leaves many gaps in our understandingof the biology of HeV and makes structure-guided drug design difficult. Structural studies of the viral RNAdependent-RNA polymerase (RdRp), which is the heart of the viral replication machinery, will set the stage for rationaldrug design and fill a major gap in our understanding of the HeV replication machinery. This review examines the currentknowledge based on the multi-domain architecture of the Hendra RdRp and highlights which essential domain functionsrepresent tangible targets for drug development against this deadly disease.

MDM2-p53 Interaction in Paediatric Solid Tumours: Preclinical Rationale, Biomarkers and Resistance by Giuseppe Barone, Deborah A. Tweddle, Jason M. Shohet, Louis Chesler, Lucas Moreno, Andrew DJ Pearson, Tom Van Maerken (114-123).
p53 is one of the main regulators of apoptosis, senescence, cell cycle arrest and DNA repair. The expression,function and stabilization of p53 are governed by a complex network of regulators including p14ARF and MDM2. MDM2is the main negative regulator of p53 activity and stability.;Unlike tumours in adults, which tend to overcome p53 regulation by p53 mutations, the paediatric tumours neuroblastomaand sarcoma frequently retain wild type p53. Nevertheless, in childhood cancer the p53 pathway is commonly impaireddue to upstream MDM2-p14ARF-p53 network aberrations. In contrast, aberrations of the p53 downstream pathway are veryrare. In cancer cells with intact p53 downstream function MDM2 inhibition, and subsequent rapid increases in nuclear p53levels, potently “re-activate” dormant apoptotic pathways and rapidly induce apoptotic cell death. As a result MDM2-p53interaction inhibitors, including cis-imidazolines analogs (Nutlins), are potentially very effective agents in neuroblastomaand sarcomas.;Predictive biomarkers are important as a lack of p53 mutations appears to reliably predict response to these inhibitors.Tumours should be screened for p53 mutations in children considered for MDM2-p53 interaction inhibitors. In addition, itis essential that other predictive biomarkers are investigated. The serum concentration of macrophage inhibitory cytokine-1 (MIC-1) may be a good pharmacodynamic biomarker based on recent findings.;In conclusion, targeting the interaction between p53 and its main negative regulator MDM2 represents a major new therapeuticapproach in poor prognosis paediatric malignancies without p53 mutations.

Introduction: Common opioids adverse effects include opioid-induced bowel dysfunction (OIBD), whichcomprises opioid-induced constipation, dry mouth, nausea, vomiting, gastric stasis, bloating, and abdominal pain. Traditionallaxatives which are often prescribed for the prevention and treatment of OIBD possess limited efficacy and displayadverse effects. A targeted approach to OIBD management is the use of a combination of an opioid agonist with opioidreceptor antagonist or administration of purely peripherally acting opioid receptor antagonists.;Methods: A literature search with terms “oxycodone/naloxone” in the PubMed and MEDLINE database updated on 31stJuly 2013. All studies of oxycodone/naloxone (randomized, controlled trials and open, uncontrolled studies) were included.In addition, studies on pharmacokinetics and pharmacodynamics of oxycodone/naloxone were included.;Results: A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet with afixed 2:1 ratio provides effective analgesia with limited disturbing effect on bowel function. Oxycodone is a valued opioidadministered either as the first strong opioid or when other strong opioids have been ineffective. Naloxone is an opioid receptorantagonist that displays local antagonist effect on opioid receptors in the gastrointestinal tract and is nearly completelyinactivated in the liver after oral administration. As demonstrated in controlled studies conducted in patients withchronic non-malignant and cancer-related pain OXN in daily doses up to 80 mg/40 mg provided equally effective analgesiawith an improved bowel function compared to oxycodone administered alone.;Conclusion: OXN is an important drug for chronic pain management, prevention and treatment of OIBD.

Despite of modern antifungal therapy, the mortality rates of invasive infection with human fungal pathogenCandida albicans are up to 40%. Studies suggest that drug resistance in the three most common species of human fungalpathogens viz., C. albicans, Aspergillus fumigatus (causing mortality rate up to 90%) and Cryptococcus neoformans (causingmortality rate up to 70%) is due to mutations in the target enzymes or high expression of drug transporter genes. Drugresistance in human fungal pathogens has led to an imperative need for the identification of new targets unique to fungalpathogens. In the present study, we have used a comparative genomics approach to find out potential target proteinsunique to C. albicans, an opportunistic fungus responsible for severe infection in immune-compromised human. Interestingly,many target proteins of existing antifungal agents showed orthologs in human cells. To identify unique proteins, wehave compared proteome of C. albicans [SC5314] i.e., 14,633 total proteins retrieved from the RefSeq database of NCBI,USA with proteome of human and non-pathogenic yeast Saccharomyces cerevisiae. Results showed that 4,568 proteinswere identified unique to C. albicans as compared to those of human and later when these unique proteins were comparedwith S. cerevisiae proteome, finally 2,161 proteins were identified as unique proteins and after removing repeats total1,618 unique proteins (42 functionally known, 1,566 hypothetical and 10 unknown) were selected as potential antifungaldrug targets unique to C. albicans.