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Biochemical Pharmacology (v.80, #5)


Molecularly targeted therapy in hepatocellular carcinoma by Hung Huynh (pp. 550-560).
Receptor tyrosine kinases presented on the cell membrane of tumor and endothelial cells and the intracellular signaling pathways are targets for antiangiogenic and antiproliferative agents.With an annual incidence of over 660,000 deaths, hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally. This disease is often diagnosed at an advanced stage, when potentially curative therapies are not feasible. HCC is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. Given the clear need, clinical development of novel therapeutic agents in HCC has begun in earnest. Our recent knowledge of the molecular mechanisms responsible of tumor initiation and progression has identified several potential molecular targets in HCC. These targets are the receptor tyrosine kinase-activated pathways, which include the Raf/MEK/ERK, PI-3K/Akt/mTOR, and Jak/Stat. Sorafenib is the multikinase inhibitor that has shown modest survival benefits in advanced HCC in two randomized controlled trials, supporting the use of molecularly targeted therapies in treatment of HCC. A number of strategies including monoclonal antibodies and tyrosine kinase inhibitors such as erlotinib, sunitinib, vandetanib, cediranib, brivanib, foretinib, and dovitinib have been developed and tested in various phases of clinical trials. The successful development of these novel targeted agents in the future will be dependent on the selection of patient populations that are most likely to derive clinical benefit, optimization of the dose used and schedules, and investigation of combined therapies. This review describes evolving molecular targeted agents, their common adverse side effects, and its potential use in management of HCC.

Keywords: Hepatocellular carcinoma; Molecular therapies; Tyrosine kinase inhibitors


BRAF as therapeutic target in melanoma by Claudia Wellbrock; Adam Hurlstone (pp. 561-567).
BRAF is a member of the RAF kinase family, which acts in the ERK/MAP kinase pathway, a signalling cascade that regulates cellular proliferation, differentiation and survival. Single point mutations can turn BRAF into an oncogene, but there appears to be a cell type/tumour specific relevance for BRAF kinase-activating mutations, since they are found predominantly in cutaneous melanoma. With the success of targeting other oncogenic kinases such as BCR-ABL, KIT or members of the epidermal-growth factor receptor (EGFR) family in other cancers, the expectations were high when the first RAF kinase-targeting drug (sorafenib) reached clinical trials. However, disappointingly the first studies using sorafenib in melanoma patients did not show the anticipated single agent efficacy. More recently, the resolution of the BRAF crystal structure has led to the development of better, more specific BRAF inhibitors such as the Plexxikon compound, PLX4032, which induced a dramatic response rate in phase I trials, validating BRAF as a clinically relevant target. In addition, our understanding of melanoma biology and the role BRAF is playing therein has improved significantly. The complexity in the ERK/MAP kinase pathway including important feedback mechanisms has been dissected, and the relevance of cross-talks with other signalling pathways has been revealed, suggesting strategies for the design of improved, more efficient combinatorial therapies. This review highlights the relevance of BRAF and the ERK/MAP kinase pathway for melanoma cell biology and discusses some of the recent advances in both, the understanding of BRAF function in melanoma and the development of improved BRAF targeting inhibitors.

Keywords: Melanoma; BRAF; MAP kinase; Sorafenib; PI3-kinase; MITF


Targeting KIT in melanoma: A paradigm of molecular medicine and targeted therapeutics by Scott E. Woodman; Michael A. Davies (pp. 568-574).
Despite multiple clinical trials utilizing a spectrum of therapeutic modalities, melanoma remains a disease with dismal outcomes in patients with advanced disease. However, it is now clear that melanoma is not a single entity, but can be molecularly divided into subtypes that generally correspond to the anatomical location of the primary melanoma. Melanomas from acral lentiginous, mucosal, and chronic sun-damaged sites frequently harbor activating mutations and/or increased copy number in the KIT tyrosine kinase receptor gene, which are very rare in the more common cutaneous tumors. Multiple case reports and early observations from clinical trials suggest that targeting mutant KIT with tyrosine kinase inhibitors is efficacious in KIT mutant melanoma. This review recounts what is known about the role of KIT in melanocyte maturation, our current understanding of KIT genetic aberrations in melanoma, and how this knowledge is being translated into clinical oncology.

Keywords: Abbreviations; KIT; c-kit gene; KIT; c-kit protein; SCF; stem cell factor; CSD; chronic sun-damaged melanoma; NCSD; non-chronic sun-damaged melanoma; IHC; immunohistochemistry; FISH; fluorescent in situ hybridizationKIT; Melanoma; Acral lentiginous; Mucosal


Targeted therapies of gastrointestinal stromal tumors (GIST)—The next frontiers by Stefan Duensing; Anette Duensing (pp. 575-583).
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract and are caused by activating KIT or PDGFRA mutations. GISTs can be successfully treated with the small molecule kinase inhibitor imatinib mesylate (Gleevec®, Novartis) with response rates of up to 85%. However, complete responses are rare, and most patients will develop imatinib resistance over time. Recent results have shown that although imatinib effectively stimulates apoptotic cell death in sensitive GIST cells, a considerable proportion of cells does not undergo apoptosis, but instead enters a state of quiescence. Quiescence is characterized by a reversible withdrawal from the cell division cycle, during which the cells remain alive and metabolically active. It is conceivable that quiescence not only plays a pivotal role in the emergence of residual disease but also in creating a pool of tumor cells that survive continuous small molecule therapy and may hence represent the “seeds” for the outgrowth of resistant clones. This review will summarize the current knowledge about GIST biology and treatment response to imatinib including the induction of cellular quiescence in GIST. In addition, we will highlight future strategies to design more effective treatment options to overcome these problems with an aim towards cure of this hitherto untreatable tumor entity.

Keywords: Gastrointestinal stromal tumors; Kinase; Targeted therapy; Small molecular inhibitor; KIT


Targeted therapy of chronic myeloid leukemia by Con Sullivan; Cong Peng; Yaoyu Chen; Dongguang Li; Shaoguang Li (pp. 584-591).
Inhibition of BCR-ABL with kinase inhibitors has become a well-accepted strategy for targeted therapy of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) and has been shown to be highly effective in controlling the disease. However, BCR-ABL kinase inhibitors do not efficiently kill leukemic stem cells (LSCs), indicating that this therapeutic strategy does not lead to a cure of CML. Development of curative therapies of CML require the identification of genes/pathways that play critical roles in survival and self-renewal of LSCs. Targeting of these key BCR-ABL downstream genes provides an opportunity to eradicate LSCs, as shown in our work that identifies the Alox5 gene as a key regulator of the function of CML LSCs. Immediate clinical trials are necessary to test the effectiveness of targeting a key BCR-ABL downstream gene in eradicating LSCs in CML patients. In this review, we will discuss current targeted therapies of CML using BCR-ABL kinase inhibitors, with a focus on the importance of developing a targeted therapy of CML through identification of target genes in CML LSCs.

Keywords: BCR-ABL; Kinase inhibitor; Leukemia stem cells; CML; Targeted therapy


Targeted therapy of thyroid cancer by Steven I. Sherman (pp. 592-601).
Systemic chemotherapies for advanced or metastatic thyroid carcinomas have been of only limited effectiveness. For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, novel therapies are needed to improve disease outcomes. Multiple novel therapies primarily targeting angiogenesis have entered clinical trials for metastatic thyroid carcinoma. Partial response rates up to 30% have been reported in single agent studies, but prolonged disease stabilization is more commonly seen. The most successful agents target the vascular endothelial growth factor receptors, with potential targets including the mutant kinases associated with papillary and medullary oncogenesis. Two drugs approved for other malignancies, sorafenib and sunitinib, have had promising preliminary results reported, and are being used selectively for patients who do not qualify for clinical trials. Additional agents targeting tumor vasculature, nuclear receptors, epigenetic abnormalities, and the immune response to neoplasia have also been investigated. Randomized trials for several agents are underway that may lead to eventual drug approval for thyroid cancer. Treatment for patients with metastatic or advanced thyroid carcinoma now emphasizes clinical trial opportunities for novel agents with considerable promise. Alternative options now exist for use of tyrosine kinase inhibitors that are well tolerated and may prove worthy of regulatory approval for this disease.

Keywords: Abbreviations; Bcr-ABL; A fusion between the Breakpoint cluster region and the; Abl; genes; DTC; differentiated thyroid carcinoma; ERK; extracellular signal regulated kinase; FGFR; fibroblast growth factor receptor; FTC; follicular thyroid carcinoma; HDAC; histone deacetylase; MAPK; Mitogen activated protein kinase; PFS; progression-free survival; PDGFR; platelet derived growth factor receptor; PI3K; phospho inositide-3 kinase; PPAR; peroxisome proliferators activator receptor; PTC; papillary thyroid carcinoma; RECIST; response evaluation criteria in solid tumors; TSH; Thyroid stimulating hormone; VEGFR; vascular endothelial growth factor receptorThyroid carcinoma; Antineoplastic agents; Angiogenesis inhibitors; Protein kinase inhibitors


The bone marrow microenvironment as a sanctuary for minimal residual disease in CML by Rajesh R. Nair; Joel Tolentino; Lori A. Hazlehurst (pp. 602-612).
Bcr-abl kinase inhibitors have provided proof of principal that targeted therapy holds great promise for the treatment of cancer. However, despite the success of these agents in treating chronic myelogenous leukemia (CML), the majority of patients continue to present with minimal residual disease contained within the bone marrow microenvironment. These clinical observations suggest that the bone marrow microenvironment may provide survival signals that contribute to the failure to eliminate minimal residual disease. The bone marrow microenvironment is comprised of multiple sub-domains which vary in cellular composition and gradients of soluble factors and matrix composition. Experimental evidence indicate that exposure of tumor cells to either bone marrow derived soluble factors or the extracellular matrix can confer a multi-drug resistance phenotype. Together, these data indicate that targeting such pathways may be a viable approach for increasing the efficacy of chemotherapy. Moreover, we propose that personalized medicine must go beyond understanding predictive models inherent to tumors but rather build predictive models that consider diversity in response due to interactions with the tumor microenvironment. Although review will focus on CML, understanding the contribution of the bone marrow microenvironment could contribute to rationale combination therapy in other types of leukemia, multiple myeloma and solid tumors which metastasize to the bone.

Keywords: Abbreviations; CML; chronic myeloid leukemia; ALL; acute lymphatic leukemia; IM; imatinib mesylate; BM; bone marrow; NI; nilotinib; DA; dasatinib; MRD; minimal residual disease; WT1; Wilms’ tumor 1; HSC; hematopoietic stem cell; HPC; hematopoietic progenitor cell; ECM; extracellular matrix; MSC; mesenchymal stromal cell; AML; acute myeloid leukemia; SLAM; signaling lymphocyte activation molecule; SDF-1; stromal cell-derived factor-1; OCT-1; organic cation transporter-1; Pgp; P-glycoprotein; GMP; granulocyte–macrophage progenitors; CAM-DR; cell adhesion-mediated drug resistance; SCF; stem cell factor; IL; interleukin; INFα; interferon-α; TGF-β; transforming growth factor-βChronic myeloid leukemia; Drug resistance; Tumor microenvironment; CAM-DR; BCR-ABL; Cancer stem cell


Targeting epidermal growth factor receptor: Central signaling kinase in lung cancer by Takeshi Yoshida; Guolin Zhang; Eric B. Haura (pp. 613-623).
Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Platinum-based doublets remain the current standard therapy for advanced NSCLC. However, overall survival (OS) has reached a plateau, even with the improvement in these regimens. Advances in the knowledge of molecular mechanisms of carcinogenesis have prompted the development of many novel molecular-targeted agents including the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Results of the recent phase III IPASS trial showed that the EGFR-TKI gefitinib has a superior progression-free survival (PFS) to the most commonly used platinum-based doublet carboplatin-paclitaxel as the first-line chemotherapy for pulmonary lung adenocarcinoma among nonsmokers in East Asia. This trial also demonstrated that the presence of EGFR mutation is the best predictor of gefitinib treatment compared with the other biomarkers including EGFR gene copy number. Despite the therapeutic benefit of EGFR-TKIs in NSCLC, most patients eventually develop resistance to these drugs. A secondary mutation of EGFR (T790M) and amplification of MET account for 70% of all cases of acquired resistance to EGFR-TKIs. This review summarizes the significance of EGFR mutations and the mechanisms of resistance to EGFR-TKIs in NSCLC, both of which are critical for patient selection to extend survival as well as to overcome resistance in NSCLC patients treated with EGFR-TKIs.

Keywords: Non-small cell lung cancer; Epidermal growth factor receptor tyrosine kinase inhibitors; Gefitinib; Erlotinib; Acquired resistance


Targeting the MAPK pathway in melanoma: Why some approaches succeed and other fail by Gajanan S. Inamdar; SubbaRao V. Madhunapantula; Gavin P. Robertson (pp. 624-637).
The Mitogen Activated Protein Kinase (MAPK) pathway plays a key role in melanoma development making it an important therapeutic target. In normal cells, the tightly regulated pathway relays extracellular signals from cell membrane to nucleus via a cascade of phosphorylation events. In melanomas, dysregulation of the MAPK pathway occurs frequently due to activating mutations in the B-RAF and RAS genes or other genetic or epigenetic modifications, leading to increased signaling activity promoting cell proliferation, invasion, metastasis, migration, survival and angiogenesis. However, identification of ideal pathway member to therapeutically target for maximal clinical benefit to melanoma patients remains a challenge. This review provides an overview of the obstacles faced targeting the MAPK pathway and why certain therapeutic approaches succeed while others fail. The review summarizes the roles played by the proteins, therapeutic potential and the drugs available to target each member of the pathway as well as concerns related to each. Potential for targeting multiple points and inhibiting other pathways along with MAPK inhibition for optimal efficacy are discussed along with explanations for development of drug resistance, which includes discussions related to cross-talk between pathways, RAF kinase isoform switching and phosphatase deregulation. Finally, the use of nanotechnology is reviewed as an approach to target the MAPK pathway using both genetic and pharmacological agents simultaneously targeting multiple points in the pathway or in combination with other cascades.

Keywords: MAPK; Melanoma; V600E; B-RAF; MEK; ERK; Resistance


Building on a foundation of VEGF and mTOR targeted agents in renal cell carcinoma by Keith T. Flaherty; Igor Puzanov (pp. 638-646).
Since late 2005 six new drugs have been approved by the Food and Drug Administration (FDA) for the treatment of metastatic renal cell carcinoma (RCC). However, the similarity of these agents with regard to mechanism of action makes it unclear if each agent has unique clinical utility. This flurry of drug development activity stems from the understanding of the central role that loss of von Hippel Lindau (VHL) gene function plays in the pathophysiology of clear cell RCC. The first agent to establish the therapeutic value of targeting the downstream consequences of VHL loss of function was a vascular endothelial growth factor (VEGF) directed monoclonal antibody, bevacizumab. Following the initial observations with bevacizumab, three VEGF receptor (VEGFR) tyrosine kinase inhibitors, with varied spectra beyond VEGFR, have been successfully developed clinically. Unanticipated clinical activity was observed with inhibitors of mTOR, a central component of the nutrient-sensing PI3 kinase pathway, in RCC. Subsequent work identified that mTOR also regulates the expression of hypoxia inducible factor (HIF), which is regulated by VHL outside of the setting of inactivating mutations or deletions. This appears to tie all of the six approved therapies to the direct consequences of loss of VHL function in clear cell RCC. It remains poorly understood to what extent these therapies differ from one another. Although the outcome of patients with metastatic RCC has been substantially altered with administration of the currently available therapies, the proper selection of currently available therapy, rational development of agents with novel mechanism of action and development of predictive biomarkers of response remains a challenge.

Keywords: Renal cell carcinoma; VHL; HIF; VEGF; Angiogenesis


Fine tuning chemotherapy to match BRCA1 status by Melissa Price; Alvaro N.A. Monteiro (pp. 647-653).
Targeted cancer therapies have been primarily directed at inhibiting oncogenes that are overexpressed or constitutively active in tumors. It is thought that as the cell's circuitry gets re-wired by the constitutive activation of some pathways it becomes exquisitely dependent on this activity. Tumor cell death normally results from inhibiting constitutively active pathways. The dependence of tumor cells on the activity of these pathways has been called oncogene addiction. Approaches that aim to exploit loss of function, rather than gain of function changes have also become a powerful addition to our arsenal of cancer therapies. In particular, when tumors acquire mutations that disrupt pathways in the DNA damage response they rely on alternative pathways that can be targeted pharmacologically. Here we review the use of BRCA1 as a marker of response to therapy with a particular focus on the use of Cisplatin and PARP inhibitors. We also explore the use of BRCA1 as a marker of response to microtubule inhibitors and how all these approaches will bring us closer to the goal of personalized medicine in cancer treatment.

Keywords: Abbreviations; DDR; DNA damage response; DSB; double stranded break; HR; homologous recombination; NER; nucleotide excision repair; NHEJ; non-homologous end joining; NSCLC; non-small cell lung carcinoma; PARP; poly ADP ribose polymerase; siRNA; small interfering RNA; SSB; single stranded breakBRCA1; DNA damage; Synthetic lethality; Cancer; Tumor suppressor; Chemotherapy


Potential therapeutic implications of cancer stem cells in glioblastoma by Lin Cheng; Shideng Bao; Jeremy N. Rich (pp. 654-665).
Glioblastoma is the most common and lethal type of primary brain tumor. Despite recent therapeutic advances in other cancers, the treatment of glioblastomas remains ineffective and essentially palliative. The treatment failure is a result of a number of causes, but we and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called glioblastoma stem cells (GSCs) display relative resistance to radiation and chemotherapy. GSCs also contribute to tumor growth through the stimulation of angiogenesis, which has been shown to be a useful therapeutic target in the treatment of recurrent or progressive malignant gliomas. Cancer stem cells also have been hypothesized as a contributor to systemic metastases. While glioblastomas rarely metastasize beyond the central nervous system, glioblastomas invade into brain structures to prevent surgical cure and GSCs have an extremely invasive phenotype. Collectively, these studies and others suggest that GSCs may be important therapeutic targets not only to achieve cure but even reduce tumor relapse and improve overall survival. Many recent studies suggest that GSCs share core regulatory pathways with normal embryonic and somatic stem cells, but display important distinctions that provide clues into useful treatment targets. The cancer stem cell hypothesis may also modify our approaches in tumor imaging and biomarker development, but clinical validation waits. In this review, we summarize the current understanding of GSC biology with a focus on potential anti-GSC therapies.

Keywords: Cancer stem cells; Glioblastoma; Molecular targeting; Tumor angiogenesis; Therapeutic resistance; Hypoxia response


Exploiting the balance between life and death: Targeted cancer therapy and “oncogenic shock” by Sreenath V. Sharma; Jeff Settleman (pp. 666-673).
Oncogene addiction can render cancer cells vulnerable to “oncogenic shock”, a transient imbalance in pro-survival and pro-apoptotic signals acutely following oncoprotein inactivation.Rational approaches to targeted cancer therapy have begun to predominate the pipelines of oncology drug development. Our rapidly increasing understanding of the “wiring” of tumor cells and the vulnerabilities of such cells that can potentially be exploited through targeted treatments has opened up enormous opportunities for improved therapies. Accumulating evidence suggests that many of these vulnerabilities reflect states of dependency or “addiction” that are unique to cancer cells (versus normal cells). Such addiction can arise due to a strict dependency on a single activated oncogene, a cell lineage-specific factor, or even to a non-oncogene, and identifying these “Achilles’ heels” within individual tumors remains an important challenge to the development of targeted therapies. Recent technology advances that facilitate high-throughput genomic analysis of tumor specimens and genome-wide RNA interference screening in cancer cell lines are key among the newly developed tools that are beginning to reveal novel context-dependent therapeutic targets, and the rapidly increasing application of these technologies by a large number of laboratories will undoubtedly lead to more effective cancer therapies in the near future. Here, we review the various forms of cancer cell addiction and their relevance to the discovery of novel therapeutic targets.

Keywords: Cancer; Oncogene addiction; Therapeutics; Kinases; Drug targets


Exploring death receptor pathways as selective targets in cancer therapy by Maria Russo; Annalisa Mupo; Carmela Spagnuolo; Gian Luigi Russo (pp. 674-682).
A recent and innovative strategy in cancer therapy is the activation of apoptosis in tumour cells specifically expressing death receptors (DR) belonging to the tumour necrosis factor (TNF) receptor superfamily and including several members known since the early ‘90. Among these, those largely studied for clinical purpose are TNF, CD95, and TRAIL receptors. Promising results are expecting from ongoing phases I/II clinical trials proving the therapeutic efficacy of DR agonistic antibodies and/or recombinant proteins alone or in association to classic and novel chemotherapeutic drugs. However, two key issues need extensive studies, before clinical and safe applications of DRs as effective anticancer drugs can be accepted: i. DR-based cancer therapy must be selective and effective against a broad range of cancers and reduce excessive systemic toxicity toward normal cells and tumour resistance after recurrent treatments; ii. an improved knowledge of mechanisms of alternative signalling triggered by DR ligands and leading to cell survival and apoptotic resistance. Activation of survival pathways regulated by key factors, such as NF-κB, JNK, p38, ERK and PI3K are the focus of several studies revealing the dark side of DR signalling. The present review focuses on new insights in the signalling and clinical application of TNF, CD95 and TRAIL receptors.

Keywords: TRAIL; CD95/Fas; TNF-alpha; Cancer therapy; Apoptosis; Death receptors


Development of small-molecule inhibitors of the group I p21-activated kinases, emerging therapeutic targets in cancer by Chunling Yi; Jasna Maksimoska; Ronen Marmorstein; Joseph L. Kissil (pp. 683-689).
The p21-activated kinases (PAKs), immediate downstream effectors of the small G-proteins of the Rac/cdc42 family, are critical mediators of signaling pathways regulating cellular behaviors and as such, have been implicated in pathological conditions including cancer. Recent studies have validated the requirement for PAKs in promoting tumorigenesis in breast carcinoma and neurofibromatosis. Thus, there has been considerable interest in the development of inhibitors to the PAKs, as biological markers and leads for the development of therapeutics. While initial approaches were based on screening for competitive organic inhibitors, more recent efforts have focused on the identification of allosteric inhibitors, organometallic ATP-competitive inhibitors and the use of PAK1/inhibitor crystal structures for inhibitor optimization. This has led to the identification of highly selective and potent inhibitors, which will serve as a basis for further development of inhibitors for therapeutic applications.

Keywords: p21-activated kinases; Organometallic; Kinase inhibitors; Breast cancer; Neurofibromatosis


Notch signaling: Emerging molecular targets for cancer therapy by Ling Yin; Omaida C. Velazquez; Zhao-Jun Liu (pp. 690-701).
The Notch signaling pathway is a highly conserved developmental pathway, which plays a critical role in cell-fate decision, tissue patterning and morphogenesis. There is increasing evidence that this pathway is dysregulated in a variety of malignancies, and can behave as either an oncogene or a tumor suppressor depending upon cell context. This review highlights the current evidence for aberration of the Notch signaling pathway in a wide range of tumors from hematological cancers, such as leukemia and lymphoma through to skin, breast, lung, pancreas, colon and brain tumors. It proposes that the Notch signaling pathway may represent novel therapeutic targets and will be a welcome asset to the cancer therapeutic arena.

Keywords: Abbreviations; ACL; adenocarcinoma of the lung; ADAM; a disintegrin and metalloprotease; AML; acute myeloid leukemia; APP; amyloid precursor protein; B-CLL; B-chronic lymphocytic leukemia; c-IAP2; cellular inhibitor of apoptosis protein 2; CSC; cancer stem cell; DBZ; dibenzazepine; DN-MAML1; dominant negative-mastermind-like 1; GBM; glioblastoma; GIT; gastrointestinal tract; GSI; γ-secretase inhibitor; HD; heterodimerization; hEGFRs; human epidermal growth factor receptors; Herp; Hes-related repressor protein; Hes; Hairy and E (spl); HIF; hypoxia-inducible-factor; LNX; ligand of Numb-protein X; MB; medulloblastoma; MMTV; mouse mammary tumor virus; NICD; Notch intracellular domain; NSCLC; non-small cell lung cancers; O; -Fut; O; -fucosyl transferase; PcG; polycomb group; PDAC; pancreatic ductal adenocarcinoma; PH; polyhomeotic; SCC; squamous cell carcinoma; T-ALL; T-cell acute lymphoblastic leukemia; TACE; TNF-α converting enzyme; TKI; tyrosine kinase inhibitor; VEGF; vascular endothelial growth factor; XIAP; X-linked inhibitor of apoptosis proteinNotch; Tumor; Tumor angiogenesis; Signal transduction; Cancer therapeutics


Striking the target in Wnt-y conditions: Intervening in Wnt signaling during cancer progression by Tura C. Camilli; Ashani T. Weeraratna (pp. 702-711).
Wnt signaling can be divided into three pathways, namely the canonical Wnt/β-catenin pathway, and the non-canonical (or heretical) Wnt/Ca2+ and planar cell polarity (PCP) pathways. Although the canonical Wnt/β-catenin pathway is the best described in cancer, increasing data points to the importance of the heretical Wnt pathways in several aspects of tumor progression. The recent advances in understanding the players and mechanisms by which these Wnt pathways contribute to cancer progression have led to the identification of numerous molecules that are already, or could be considered, targets for cancer therapy.

Keywords: Wnt; Wnt5A; Calcium; PCP; β-Catenin; Cancer


Small molecule modulation of HH-GLI signaling: Current leads, trials and tribulations by Christophe Mas; Ariel Ruiz i Altaba (pp. 712-723).
Many human sporadic cancers have been recently shown to require the activity of the Hedgehog-GLI pathway for sustained growth. The survival and expansion of cancer stem cells is also HH-GLI dependent. Here we review the advances on the modulation of HH-GLI signaling by small molecules. We focus on both natural compounds and synthetic molecules that target upstream pathway components, mostly SMOOTHENED, and those that target the last steps of the pathway, the GLI transcription factors. In this review we have sought to provide some bases for useful comparisons, listing original assays used and sources to facilitate comparisons of IC50 values. This area is a rapidly expanding field where biology, medicine and chemistry intersect, both in academia and industry. We also highlight current clinical trials, with positive results in early stages. While we have tried to be exhaustive regarding the molecules, not all data is in the public domain yet. Indeed, we have opted to avoid listing chemical structures but these can be easily found in the references given. Finally, we are hopeful that the best molecules will soon reach the patients but caution about the lack of investment on compounds that lack tight IP positions. While the market in developed nations is expected to compensate the investment and risk of making HH-GLI modulators, other sources or plans must be available for developing nations and poor patient populations. The promise of curing cancer recalls the once revered dream of El Dorado, which taught us that not everything that GLI-tters is gold.

Keywords: Hedgehog; GLI; Smoothened; Cancer; Small molecule


Current strategies to target p53 in cancer by Fang Chen; Wenge Wang; Wafik S. El-Deiry (pp. 724-730).
Tumor suppressor p53 is a transcription factor that guards the genome stability and normal cell growth. Stresses like DNA damage, oncogenic assault will turn on p53 function which leads to cell cycle arrest for DNA repair, senescence for permanent growth arrest or apoptosis for programmed cell death. At the late stage of cancer progression, p53 is hijacked in all forms of tumors either trapped in the negative regulator such as MDM2/viral proteins or directly mutated/deleted. Re-introduction of a functional p53 alone has been proven to induce tumor regression robustly. Also, an active p53 pathway is essential for effective chemo- or radio-therapy. The emerging cyclotherapy in which p53 acts as a chemoprotectant of normal tissues further expands the utility of p53 activators. Functionally, it is unquestionable that drugging p53 will render tumor-specific intervention. One direct method is to deliver the functional wild-type (wt) p53 to tumors via gene therapy. The small molecule strategies consist of activation of p53 family member such as p73, manipulating p53 posttranslational modulators to increase wt p53 protein levels, protein–protein interaction inhibitors to free wt p53 from MDM2 or viral protein, and restoring p53 function to mutant p53 by direct modulation of its conformation. Although most of the current pre-clinical leads are in μM range and need further optimization, the success in proving that small molecules can reactivate p53 marks the beginning of the clinical development of p53-based cancer therapy.

Keywords: p53 Signaling; Cancer


Molecular imaging and targeted therapies by David L. Morse; Robert J. Gillies (pp. 731-738).
Targeted therapeutic and imaging agents are becoming more prevalent, and are used to treat increasingly smaller segments of the patient population. This has lead to dramatic increases in the costs for clinical trials. Biomarkers have great potential to reduce the numbers of patients needed to test novel targeted agents by predicting or identifying non-response early-on and thus enriching the clinical trial population with patients more likely to respond. Biomarkers are characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers can be used to predict response to specific therapies, predict response regardless of therapy, or to monitor response once a therapy has begun. In terms of drug development, predictive biomarkers have the greatest impact, as they can be used as inclusion criteria for patient segmentation. Prognostic markers are used routinely in clinical practice but do not provide direction for the use of targeted therapies. Imaging biomarkers have distinct advantages over those that require a biopsy sample in that they are “non-invasive” and can be monitored longitudinally at multiple time points in the same patient. This review will examine the role of functional and molecular imaging in predicting response to specific therapies; will explore the advantages and disadvantages of targeting intracellular or extracellular markers; and will discuss the attributes of useful targets and methods for target identification and validation.

Keywords: Biomarker; Targeted therapy; Intracellular; Extracellular; Target


Methods for investigation of targeted kinase inhibitor therapy using chemical proteomics and phosphorylation profiling by Bin Fang; Eric B. Haura; Keiran S. Smalley; Steven A. Eschrich; John M. Koomen (pp. 739-747).
Phosphorylation acts as a molecular switch for many regulatory events in signaling pathways that drive cell division, proliferation, and apoptosis. Because of the critical nature of these protein post-translational modifications in cancer, drug development programs often focus on inhibitors for kinases and phosphatases, which control protein phosphorylation. Numerous kinase inhibitors have entered clinical use, but prediction of their efficacy and a molecular basis for patient response remain uncertain. Chemical proteomics, the combination of drug affinity chromatography with mass spectrometry, identifies potential target proteins that bind to the drugs. Phosphorylation profiling can complement chemical proteomics by cataloging modifications in the target kinases and their downstream substrates using phosphopeptide enrichment and quantitative mass spectrometry. These experiments shed light on the mechanism of disease development and illuminate candidate biomarkers to guide personalized therapeutic strategies. In this review, commonly applied technologies and workflows are discussed to illustrate the role of proteomics in examining tumor biology and therapeutic intervention using kinase inhibitors.

Keywords: Phosphorylation; Phosphoproteomics; Mass spectrometry; Drug response; Drug resistance; Targeted therapy


Identification of novel pancreatic adenocarcinoma cell-surface targets by gene expression profiling and tissue microarray by David L. Morse; Yoga Balagurunathan; Galen Hostetter; Maria Trissal; Narges K. Tafreshi; Nancy Burke; Mark Lloyd; Steven Enkemann; Domenico Coppola; Victor J. Hruby; Robert J. Gillies; Haiyong Han (pp. 748-754).
Pancreatic cancer has a high mortality rate, which is generally related to the initial diagnosis coming at late stage disease combined with a lack of effective treatment options. Novel agents that selectively detect pancreatic cancer have potential for use in the molecular imaging of cancer, allowing for non-invasive determination of tumor therapeutic response and molecular characterization of the disease. Such agents may also be used for the targeted delivery of therapy to tumor cells while decreasing systemic effects. Using complementary assays of mRNA expression profiling to determine elevated expression in pancreatic cancer tissues relative to normal pancreas tissues, and validation of protein expression by immunohistochemistry on tissue microarray, we have identified cell-surface targets with potential for imaging and therapeutic agent development. Expression profiles of 2177 cell-surface genes for 28 pancreatic tumor specimens and 4 normal pancreas tissue samples were evaluated. Expression in normal tissues was evaluated using array data from 103 samples representing 28 organ sites as well as mining published data. One-hundred seventy unique targets were highly expressed in 2 or more of the pancreatic tumor specimens and were not expressed in the normal pancreas samples. Two targets (TLR2 and ABCC3) were further validated for protein expression by tissue microarray (TMA) based immunohistochemistry. These validated targets have potential for the development of diagnostic imaging and therapeutic agents for pancreatic cancer.

Keywords: Cell-surface; Biomarker; Cancer; Imaging; Expression profiling


Using genetics and genomics strategies to personalize therapy for cancer: Focus on melanoma by Katherine L. Nathanson (pp. 755-761).
Individualizing therapeutic selection for patients is a major goal in cancer treatment today. This goal is best facilitated by understanding both an individual's inherited genetic variation and the somatic genetic changes arising during cancer development. Clinical decision making based on inherited genetic variation is done for those patients with cancer susceptibility syndromes and more generally to personalize drug dosing. Personalized medicine based on genetic and genomic changes within tumors is being applied more widely, with increased use of therapies targeted to somatic mutations and amplifications. Somatic mutations associated with resistance also are being used to select against therapies. Somatic point mutation testing being used clinically includes direct sequencing, short sequencing and single nucleotide interrogation. Single amplifications are commonly assessed using FISH or CISH; high throughput assessment of amplifications and deletions is done mainly on a research basis. Melanomas contain complex mutational profiles that allow them to be sub-grouped by their genetic and genomic profile, each of which then can be evaluated pre-clinically to determine their response to targeted therapies. BRAF V600E mutations are the most common found in melanoma; specific inhibitors of mutant BRAF have been developed and are currently in clinical trials. In addition, other melanoma sub-groups have been identified genetically, which respond to other inhibitors. These studies focus on somatic genetic changes in cancer, which can be targeted directly by therapies. However in the future, personalized medicine will use a combination of inherited and somatic genetics to select the optimal tailored therapy for each patient.

Keywords: Personalized medicine; Melanoma; Targeted therapy; Mutation detection; Somatic genetics


The benefits and challenges associated with the use of drug delivery systems in cancer therapy by Edna Cukierman; David R. Khan (pp. 762-770).
The use of drug delivery systems as nanocarriers for chemotherapeutic agents can improve the pharmacological properties of drugs by altering drug pharmacokinetics and biodistribution. Among the many drug delivery systems available, both micelles and liposomes have gained the most attention in recent years due to their clinical success. There are several formulations of these nanocarrier systems in various stages of clinical trials, as well as currently clinically approved liposomal-based drugs. In this review, we discuss these drug carrier systems, as well as current efforts that are being made in order to further improve their delivery efficacy through the incorporation of targeting ligands. In addition, this review discusses aspects of drug resistance attributed to the remodeling of the extracellular matrix that occurs during tumor development and progression, as well as to the acidic, hypoxic, and glucose-deprived tumor microenvironment. Finally, we address future prospective approaches to overcoming drug resistance by further modifications made to these drug delivery systems, as well as the possibility of coencapsulation/coadministration of various drugs aimed to surmount some of these microenvironmental-influenced obstacles for efficacious drug delivery in chemotherapy.

Keywords: Liposomes; Micelles; Extracellular matrix; Drug delivery; Chemotherapy; Tumor microenvironment; Nanocarriers
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