A study recently published in The New England Journal of Medicine (Jun 1st, 2013) identified an acquired mutation in the ROS1 kinase domain resulting in resistance to crizotinib in a woman with metastatic lung adenocarcinoma.

Crizotinib is an oral ATP-competitive selective Non Small cell Lung Cancer resized 600inhibitor of the anaplastic lymphoma kinase (ALK) and MET tyrosine kinase that inhibits tyrosine phosphorylation of activated ALK at nanomolar concentrations. In 2011, crizotinib was approved by the U.S. Food and Drug Administration (FDA) for treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) that are ALK-positive. Activating mutations or translocations of the ALK gene have been discovered in various types of cancer, including anaplastic large-cell lymphoma, neuroblastoma, inflammatory myofibroblastic tumor, and non–small-cell lung cancer. Because of its role in lung cancer, ALK receptor tyrosine represents a potential therapeutic target.

In addition to ALK mutations or translocations, chromosomal rearrangements in another tyrosine kinase receptor, ROS1, was identified in a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib was found highly sensitive in lung cancer patients who harbor rearrangements in ALK or ROS1. However, resistance to crizotinib was reported in lung cancer due to secondary mutations in ALK. To overcome this problem a new compound CH5424802 has been identified and is currently in clinical trials ( number, NCT01588028) for ALK-positive NSCLC.

A 48-year-old woman with metastatic lung cancer and a distant history of light smoking was initially treated with first line of chemotherapy with carboplatin and pemetrexed. Genetic analysis with patient’s cancer cells showed no mutation in oncogenic KRAS or EGFR and no ALK translocations. Additional molecular testing revealed ROS1 rearrangement lead to expression of a fusion protein CD74-ROS1. After three cycles of chemotherapy, marked disease progression was noted and patient’s condition deteriorated. The patient was then enrolled in a clinical trial evaluating the safety and efficacy of crizotinib in cancer patients with ROS1 translocations ( number, NCT00585195). Computed tomographic scan (CT) obtained two months after treatment noted dramatic response to treatment. However, one month later, while the patient was still taking crizotinib, disease progression was observed and unfortunately the patient expired. Molecular analysis of tumor samples from all sites of disease detected a mutation glycine to arginine Gly2032Arg (G2032R) spanning CD74-ROS1 fusion area that had not been observed in pretreated samples. No other mutation of ROS1 kinase was identified by deep sequencing. Thus this suggested that appearance of G2032R mutation was an early event in crizotinib-resistant tumor cells.

To identify role of G2032R mutation in crizotinib resistance, 293T cells were transfected with either mutated or nonmutated G2032R CD74-ROS1 and subsequently treated with tyrosine kinase inhibitors crizotinib and TAE648. Cells transfected with a mutated form of ROS1 exhibited a half-maximal inhibitory concentration (IC50) value greater than 1000 nM while for nonmutated cells it was approximately 30 nM for crizotinib and 50 nM for TAE648. Crystal structure analysis of ROS1 revealed an arginine at position 2032 resulted in steric interference of crizotinib binding. Collectively, this study reported a mechanism of acquired resistance to crizotinib in a cancer driven by oncogenic ROS1 fusion. Therefore, in the context of these observations, it may be necessary to identify novel compounds that specifically target the G2032R ROS1 mutant to overcome the development of crizotinib resistance in cancers driven by ROS1.


1. Awad MM, Katayama R, McTigue M, et al. Acquired Resistance to Crizotinib from a Mutation in CD74-ROS1. N Engl J Med 2013.

2. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-70.

3. Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 2011;19:679-90.

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Arup Chakraborty is postdoctoral research fellow at the National Cancer Institute, Bethesda, MD. He earned a doctoral degree from Texas Tech University, and his primary research interest is in the field of clinical cancer mainly in mechanisms of resistance to molecularly targeted therapies


Upcoming Oncology Conferences and Events: Sept-Nov, 2013

This listing includes upcoming Oncology-related conferences from September – November, 2013.



Current Trends in Urological Cancer

September 11, 2013

Wolfson Centre, The Medical School, University of Birmingham

Edgbaston, United Kingdom

Advance registration deadline: August 14, 2013

Advances in Ovarian Cancer Research: From Concept to Clinic

September 18-21, 2013

J.W. Marriott Marquis Miami

Miami, FL

Abstract submission deadline: July 8, 2013

Advance registration deadline: August 5, 2013

Cancer Vaccines

September 18-19, 2013

London, United Kingdom

Frontiers in Basic Cancer Research

September 18-22, 2013

Gaylord National Resort and Convention Center

National Harbor, MD

Abstract submission deadline: July 9, 2013

Advance registration deadline: August 6, 2013

Cancer Advance at Harvard Medical School

September 19, 2013

Harvard Medical School

Boston, MA

Clinical Genomics for Cancer Management Conference

September 23-24, 2013

Seaport Hotel

Boston, MA

Abstracts due: August 23, 2013

Advance registration deadline: August 23, 2013

17th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress

September 27th to October 1st 2013

Amsterdam, Netherlands

Advance registration deadline: Aug 6, 2013

Late Breaking Abstract Submission Deadline: Aug 7, 2013



UAE Cancer Congress 2013

October 3-5, 2013

InterContinental Festival City

Dubai, UAE

Abstract Submission Deadline: June 30, 2013

Early Registration Deadline: August 31, 2013

Cancer Epigenomics

October 6-8, 2013

Melia, Sitges, Spain

Abstract submission deadline June 21, 2013

Early Registration Deadline: August 2, 2013

4th International Conference on Stem Cells and Cancer (ICSCC-2013): Proliferation, Differentiation and Apoptosis

October 19-22, 2013

Mumbai, India

Abstract Submission Deadline: June 30, 2013

Early Registration Deadline: June 30, 2013

15th World Conference on Lung Cancer

October 27-30, 2013

Sydney Australia

Abstract Submission Deadline:  June 21, 2013

Early Registration Deadline: August 2, 2013


Bioactive Lipids in Cancer, Inflammation and Related Diseases

November 3 – 6, 2013

San Juan, Puerto Rico

Abstract Submission Deadline: August 23, 2013

Early Registration Deadline: August 16, 2013

Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes

November 3-6, 2013

Westin Gaslamp Quarter

San Diego, CA

Abstract submission deadline: August 28, 2013

Advance registration deadline: September 26, 2013

The Translational Impact of Model Organisms in Cancer

November 5-8, 2013

Omni San Diego

San Diego, CA

Abstract submission deadline: August 26, 2013

Early registration deadline: September 23, 2013

Translational Cancer Research for Basic Scientists

November 10-15, 2013

Omni Parker House Hotel

Boston, Massachusetts

Application deadline: May 13, 2013


Websites that list upcoming Conferences & Events in Oncology:

American Association for Cancer Research

Conference Alerts: Academic Conferences Worldwide

Genentech BioOncology


Melanoma is a type of skin cancer that arises from specialized pigmented cells in our body known as melanocytes, which are responsible for the production of melanin (a pigment responsible for skin and hair color). Because most melanoma cells still make melanin, melanoma tumors are usually brown or black. It accounts for 4% of all skin cancers; however, it is responsible for the largest number of skin cancer related deaths in the world. In the U.S, according to the national cancer institute, estimated new cases and deaths from melanoma in 2013 will be 76,690 and 9,480 respectively (for details please refer to my blog titled “targeting B-RAF kinase in melanoma”).

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BRAF is a serine/threonine protein kinase that activates the mitogen activated protein kinase (MAPK) signaling pathway. Approximately 50% of melanomas harbor activating BRAF mutations among which mutations at codon 600, resulting in substitution of glutamic acid for valine (B-RAFV600E), are the most prevalent. Activated BRAF phosphorylates and activates mitogen-activated protein kinase kinase proteins (MEK1 and MEK2), which then activate downstream MAP kinases. The MAPK pathway is implicated in the regulation of proliferation and survival of tumor cells in many cancers. This suggests that both B-RAF and its downstream MEK kinase could serve as attractive targets in cancer therapeutics. In 2011, the U.S. Food and Drug Administration (FDA) approved vemurafenib for the treatment of V600E B-RAF mutated melanoma patients. As a single agent, vemurafenib resulted in some degree of tumor regression among 90% of melanoma patients early in the course of treatment. Continuing with the effort to target B-RAF and MEK, several studies tested the efficacy of other compounds to inhibit these components of the MAPK pathway. Based on international clincal trials, on May 29th, 2013, the U.S FDA approved two new drugs Tafinlar (dabrafenib) and Mekinist (trametinib) for use in advanced melanomas with B-RAF V600E mutation. Mekinist is also approved for another form of B-RAF mutilated patients, V600K, which accounts for approximately 10% of B-RAF mutated metastatic melanoma. The mutation status of the melanoma patients are detected by an FDA-approved test, such as companion diagnostic assay from bioMerieus S.A., and THxID-B-RAF.

Tafinlar (dabrafenib) is an orally bioavailable B-RAF-inhibitor which selectively binds to and inhibits the activity of mutated B-RAF (V600E). The FDA approval of dabrafenib is based on an open label multicenter phase III study where 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Dacarbazine is an alkylating agent which is also use to treat malignant melanoma. The study observed a statistically significant increase in progression-free survival (PFS) in patients treated with dabrafenib, compared to dacarbazine. With dabrafenib, the median PFS was 5.1 months and overall response rate was 52%. The most common adverse reactions with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache.

Trametinib is an orally bioavailable inhibitor of MEK which specifically binds to and inhibits MEK 1 and 2, resulting in an inhibition of growth factor-mediated cell signaling and cellular proliferation in various cancers. The FDA approval of trametinib is based on the phase 3 open-label trials which randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib or dacarbazine or paclitaxel (a mitotic inhibitor used in cancer chemotherapy). The study observed a statistically significant increase in PFS in trametinib treated patients compared to other treatments. The PFS was 4.8 month for patients treated with trametinib, while with other chemotherapeutic treatments it was 1.5 months. Rash, diarrhea, and peripheral edema were the most common toxic effects noted following trametinib treatment.

GlaxoSmithKline, manufacturer of both new drugs, reported that the products would be available no later than the early part of the third quarter of 2013.


Hepatocellular carcinoma (HCC) is an aggressive form of primary liver cancer that occurs more frequently in men than women. This malignancy is different from metastatic liver cancer which originates in another organ (such as the breast or colon) and then spreads to the liver. Even though the incidence of this malignancy is exceptionally high in Asia and Africa, the number of new cases in America and Europe is rapidly increasing, making HCC a worldwide health problem. In spite of improvements in treatment, patients with HCC continue to have a poor prognosis, with 5-year survival rates of only 18%. Therefore, in order to formulate sustained therapeutic strategies, detailed understanding of the molecular network of aggressive HCC is required.

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In addition to significant genomic and proteomic alterations, cancer cells also exhibit highly unique metabolic phenotype which is characterized by increased glucose uptake, enhanced glycolytic activity, decreased mitochondrial activity, low bioenergetic status, and aberrant phospholipid metabolism. This suggests that metabolism may also play a significant role in differentiating normal cells from neoplastic tissues. Several metabolic markers of malignancy are described in particular tumors, such as N-acetyl aspartate and myo-inositol in brain cancers, citrate in prostate cancer, or triglycerides in liposarcomas, based on tissue-specific biochemistry. Cancer metabolite profiling, or cancer metabolomics, is a promising novel approach to help understand the biological events associated with cancer development and progression. A systemic analysis of the pathways in which these genes and biochemical molecules interact may assist in the identification of key biomarkers or drug targets for clinical intervention. Metabolite detection and quantification is usually carried out by nuclear magnetic resonance (NMR) spectroscopy, while mass spectrometry (MS) provides another highly sensitive metabolomics technology.

Using a combination of gene expression and metabolic profile analysis, a recent study by Budhu et al. (2013) reported identification of lipid biomarkers, monounsaturated lipid metabolite (MUPA) and stearoyl-CoA-desaturase (SCD), as key role players in a subset of HCC termed as hepatic stem cell HCC (HpSC-HCC). HpSC-HCC was found to exhibit stem cell–like gene expression traits and associated with poor prognosis as reported by Yamashita and colleagues. By performing metabolomics profiling of tumor and non-tumor tissue samples from 356 patients, Budhu et al. identified 28 metabolites and 169 genes associated with aggressive HCC. Using an integrative data analysis approach to determine gene-metabolite interconnections, this study suggested genes associated with fatty-acid metabolites may play roles in overall survival, stem cell-like HCC and metastasis-related prognosis. Higher expression of one of the genes stearoyl-CoA-desaturase (SCD) was found to be associated with worse survival and disease-free survival. SCD codes for an enzyme responsible for conversion of saturated palmitic acid (SPA) to its monounsaturated form, palmitoleic acid (MUPA). Based on these results, Budhu and colleagues sought to determine the mechanism by which SCD and its related fatty acids, MUPA and SPA, functionally contribute to aggressive HCC and how altering SCD activity may improve this effect. They noted elevated levels of MUPA in aggressive HCCs, and that MUPA enhanced migration and invasion of cultured HCC cells and colony formation by HCC cells, Huh7. Furthermore, HCC cells that had reduced SCD had decreased migration and colony formation in culture and reduced tumorigenicity in mice. Collectively this study suggested that SCD and its related metabolites may be valuable biomarkers and prognostic indicators for molecular re-staging of HCC.



1. Griffin JL, Shockcor JP. Metabolic profiles of cancer cells. Nat Rev Cancer 2004;4:551-61.

2. Griffin JL, Kauppinen RA. A metabolomics perspective of human brain tumours. FEBS J. 2007;274:1132-9.

3. Costello LC, Franklin RB. ‘Why do tumour cells glycolyse?’: from glycolysis through citrate to lipogenesis. Mol Cell Biochem. 2005;280:1-8.

4. Serkova NJ, Glunde K. Metabolomics of cancer. Methods Mol Biol. 2009;520:273-95.

5. Budhu A, Roessler S, Zhao X, et al. Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes. Gastroenterology. 2013;144:1066-1075.e1.

6. Yamashita T, Ji J, Budhu A, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136:1012-24.


Endometrial cancer (EC) is the seventh most commonly diagnosed cancer among women, with 189,000 new cases and 45,000 deaths occurring worldwide each year. In the United States, it is the fourth most commonly diagnosed cancer among women. According to the national Cancer Institute (NCI, USA), in 2013 approximately 50,000 women will be diagnosed with endometrial cancer, with more than an estimated 8,000 deaths from the disease.describe the image

Endometrial cancers are classified into two types: endometrioid (type I) and serous (type II). Type I EC is a less severe form. Risk factors include obesity, anovulation, nulliparity, and exogenous estrogen exposure. This type of EC commonly express both estrogen and progesterone receptors. Clinically, type I EC is more often a low-grade tumor with a favorable prognosis.

On the contrary, type II EC is a more life-threatening form and not associated with estrogen exposure. Clinically, this type of EC is marked by an aggressive clinical course, and has a tendency for early spread and poor prognosis. Endometroid (type I) tumors are treated with adjuvant radiotherapy, whereas serous (type II) tumors are treated with chemotherapy. Even though EC is one of the most common pelvic gynecologic malignancies in the world, to date no targeted therapies are available to treat patients.

Therefore, in order to formulate an efficient treatment plan, detailed genomic characterization of primary and metastatic endometrial cancers are required. Several studies have reported numerous genetic changes associated with endometrial cancer. Type I endometrial carcinomas involve mutations in PTEN, KRAS, FGFR2, PIK3CA and β-catenin, as well as defects in DNA mismatch repair. Type II endometrial carcinomas frequently show aneuploidy and TP53, PIK3CA, and PPP2R1A gene mutations. Using whole exome DNA sequencing on 13 primary serous EC patients, a study by Bell and colleagues (2012) identified high frequency somatic mutations in CHD4, FBXW7, and SPOP genes (associated with chromatin-remodeling and ubiquitin ligase complex). These mutations may play a significant role as driver mutations (gene mutations implicated in cancer initiation and progression) in serous EC.

To better understand the molecular alterations associated with endometrial cancer, a recent study was performed by The Cancer Genome Atlas Research Network (TCGA) using integrated genomic and proteomic analysis appearing in a recent issue of Nature journal (May 2nd, 2013).

Using a multiplatform analysis approach on 373 endometrial carcinomas including low-grade endometroid, high-grade endometroid, and serous carcinomas this study provided key molecular insight into the classification of endometrial cancer. This new study classified endometrial cancer into four new categories:

* The POLE group contained ultrahigh mutation rates in the POLE gene (involved in cellular metabolism) and frequent activation of the WNT/CTNNB1 signaling pathway

* The hypermutated microsatellite instability group showed a high mutation rate, as well as few copy number alterations, and reduced expression of DNA mismatch repair gene MLH1

* The copy-number low group showed increased expression of progesterone receptor and DNA repair protein RAD50

* The copy-number high group composed of mostly serous tumors and serous-like endometroid tumors and exhibited increased transcriptional activity of cell cycle related genes (MYC, CCNE1, PIK3CA, CDKN2A etc.) and a mutation in tumor suppressor gene TP53.

In addition, this study also observed compelling similarities in the molecular phenotype between 25% of high-grade endometroid tumors and uterine serous carcinoma, suggesting that this genome-based molecular characterization may benefit these patients. Overall, this new molecular characterization might facilitate the discovery of effective, targeted treatments as well as may affect post-surgical adjuvant treatment for women with endometrial cancer.


Bansal N, Yendluri V, Wenham RM (2009) The molecular biology of endometrial cancers and the implications for pathogenesis, classification, and targeted therapies. Cancer Control 16: 8-13.

Hecht JL, Mutter GL (2006) Molecular and pathologic aspects of endometrial carcinogenesis. J Clin Oncol 24: 4783-4791.

Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, Yau C, Laird PW, Ding L, Zhang W, Mills GB, Kucherlapati R, Mardis ER, Levine DA, Network CGAR (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497: 67-73.

Kuhn E, Wu RC, Guan B, Wu G, Zhang J, Wang Y, Song L, Yuan X, Wei L, Roden RB, Kuo KT, Nakayama K, Clarke B, Shaw P, Olvera N, Kurman RJ, Levine DA, Wang TL, Shih IM (2012) Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. J Natl Cancer Inst 104: 1503-1513.

Le Gallo M, O’Hara AJ, Rudd ML, Urick ME, Hansen NF, O’Neil NJ, Price JC, Zhang S, England BM, Godwin AK, Sgroi DC, Hieter P, Mullikin JC, Merino MJ, Bell DW, Program NISCNCS (2012) Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet 44: 1310-1315.


In recent years, “targeted” cancer therapies have shown promising results. With the discovery and development of “personalized” novel cancer treatments encouraging clinical responses in a subset of patients with advanced systemic disease have been observed.

This has been particularly evident with several of the recently developed kinase inhibitors that target oncogenic forms of EGFR, HER2, BCR-ABL, ALK, JAK2, and BRAF. In addition, several MEK inhibitors are developed to target oncogenic RAS. Although these drugs initially exhibit responses, they fail to sustain results due to the emergence of acquired resistance. The median duration of response with the EGFR inhibitor gefitinib (Iressa®, FDA approved) in non-small cell lung cancer patients is 7 months. Additionally, response duration for the BRAF inhibitor vemurafenib is approximately 6-7 months.  In phase II clinical trials, median progression free survival time in patients bearing K-RAS mutant tumors treated with selumetinib (MEK inhibitor) was 5.3 months. Multiple mechanisms are associated to limiting the efficacy of these targeted agents. Therefore, further studies are needed to develop effective strategies to overcome the aquisition of resistance to targeted agents. Formulation of effective drug combinations as well as identification of novel compounds with anti-neoplastic properties could be useful in this context.


MEK signal transduction

A recent study by Morris and colleagues published in Cancer Discovery (April 29th, 2013) reported the identification and characterization of a novel and selective ERK inhibitor. This inhibitor was found to induce tumor regression in BRAF, NRAS, and KRAS xenograft models and also inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor resistant models. In addition, this ERK inhibitor was found to be effective in tumor cells that are resistant to concurrent treatment with BRAF and MEK inhibitors.

In this study, Morris et al. screened nearly 5 million compounds’ ability to bind the unphosphorylated form of ERK2 and observed ATP competitive compound, SCH772984, selectively bound and inhibited ERK1/2 activity at a nanomolar range. SCH772984 was effective in blocking ERK activation in a dose-dependent manner in V600EBRAF mutant and KRAS mutant cell lines. A known mechanism of resistance to MAPK inhibitors is via negative feedback activation of the MAPK pathway through ERK activation (for details please refer to my previous post titled “resistance to BRAF inhibitors in melanoma”). In this study, negative feedback activation via increased ERK phosphorylation was also observed following treatment with SCH772984. However, SCH772984 was found to be effective in blocking further downstream signaling of ERK as it maintained complete inhibition of ERK substrate p90 ribosomal S6 kinase.

Next, to test the efficacy of SCH772984 in the context of clinically observed resistance mechanisms to the MAPK inhibitors (such as BRAF amplification, MEK1 mutation, RAS mutation), researchers generated resistant cell lines and tested the efficacy of SCH772984. In all scenarios tested, sensitivity to SCH772984 treatment was observed as compared to the MAPK inhibitors. A recent clinical study concurrently treated patients with BRAF and MEK inhibitors and found to double the progression free survival period in patients whose tumors harbored MAPK activation especially in V600EBRAF mutant melanoma.

In the near future this combination could potentially become the standard-of-care for V600EBRAF mutant melanoma. However, due to heterogeneous nature of tumor cells, it is possible that acquired resistance may emerge to this combination treatment. To that end, Morris et al. tested the efficacy of SCH772984 in BRAF and MEK inhibitor combination resistant models of melanoma and colorectal cancer. Reduced activation of ERK and inhibition of cellular proliferation was noted in this model following SCH772984 treatment.

Taken together this study implicates a new ERK inhibitor SCH772984 that may exhibit encouraging therapeutic responses for the treatment of patients with BRAF, NRAS, and KRAS mutations including patients who relapse on current BRAF or MEK inhibitor therapy.


1. Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D. MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:27.

2. Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist. 2003;8:303-6.

3. Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov. 2013.


Acute myeloid leukemia (AML), a cancer of hematopoietic cells, is a molecularly heterogeneous disease. AML is associated with several genetic changes that alter normal hematopoietic growth and differentiation, resulting in the accumulation of large numbers of abnormal immature myeloid cells in the bone marrow and peripheral blood. These cells are capable of dividing and proliferating, but cannot differentiate into mature hematopoietic cells. Recurrent structural alterations of chromosomes are the established diagnostic and prognostic markers in AML. Several studies using targeted sequencing (determination of DNA sequence of specific areas of interest within the genome) identified recurrent gene mutations that contained diagnostic and prognostic information, including mutations in FLT3, NPM1, KIT, CEBPA, and TET2 genes. In addition, massively parallel sequencing (high-throughput approaches of DNA sequencing, also called next-generation sequencing) has discovered recurrent mutations in DNMT3A and IDH1/2 genes that may also provide prognostic information for some patients. Even though these genetic abnormalities may play an essential role in the pathogenesis of AML, nearly 50% of AML patients have normal karyotype (an organized profile of a person’s chromosomes).No. of mutations in AML resized 600 Based on the cytogenetic analysis, AML patients are classified into three major risk categories: favorable, intermediate and unfavorable. AML patients with PML-RARA, RUNX1-RUNX1T1, or MYTH11-CBFB gene fusions (as a result of chromosomal rearrangements) profile belong to favorable- risk category and have shown relatively good response to chemotherapy. Patients with complex genetic alterations (e.g. monosomy karyotype) are categorized into unfavorable-risk profile. Majority of the AML patients exhibit normal karyotype and belong to intermediate-risk category. Some of these patients respond well to chemotherapy while others don’t. Since nearly 50% of AML patients have normal chromosomal profile, better molecular characterization of pathogenesis of AML is required for better approaches to therapy. In addition, next-generation sequencing (NGS) studies have revealed that even though AML usually harbor hundreds of mutated genes, only a limited number of mutated  genes serve as driver mutations (i.e. causing the tumor). Among the different adult cancer types sequenced extensively so far, AML has had the fewest mutations discovered. Therefore, identification of a significant number of novel driver mutations present at low frequency in AML will help to better understand the leukemogenesis.

A study recently published in the New England Journal of Medicine (May 1st, 2013) by researchers at The Cancer Genome Atlas (TCGA) group led by Timothy J. Ley broadly classified the genomic alterations that frequently underlie the development of AML. This study also suggested potential new drug targets and treatment strategies for AML. In this study the genome of 200 newly diagnosed adult cases of AML patients, representing all of the known subtypes, was analyzed by performing whole-genome sequencing (50 cases) and whole-exome sequencing (150 cases). In addition, RNA and micro-RNA sequencing and DNA-methylation analysis was also performed. 

Each AML genome was compared to the describe the imagenormal genome derived from a skin sample of the same patient. The recurrently mutated genes discovered in this study were grouped into nine categories that were defined according to biologic function and that are considered to play a role in AML pathogenesis. Some of these groups include: tumor suppressor genes, transcription-factor fusions, activated signaling genes and epigenetic modifiers (DNA-methylation related genes and chromatin-modifying genes) with the latter being the most frequently mutated class of genes found in this study. At least one potential driver mutation was identified in nearly all AML samples including genes that are well established as being associated with AML pathogenesis (eg. FLT3, NPM1, DNMT3A, IDH1, IDH2, and CEBPA).

This study was the first to observe recurrent mutations in cohesin genes, which are important in cell division, in 13% of cases of AML samples. In addition, this study also observed a mutation in microRNA 142 (miR-142). Overall this study provided a detailed understanding of the genetic and epigenetic changes associated with adult de novo AML. Future studies are warranted to understand the relationship between these alterations and treatment results.



1. Bacher U, Schnittger S, Haferlach T. Molecular genetics in acute myeloid leukemia. Curr Opin Oncol. 2010;22:646-55.

2. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650-65.

3. Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi YL, et al. Array-based genomic resequencing of human leukemia. Oncogene. 2010;29:3723-31.

4. Network TCGAR. Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. N Engl J Med. 2013.


A brain tumor is an abnormal growth of tissue in the brain. Brain tumors may develop from neural elements within the brain (primary brain tumor), or they may represent spread of distant cancers (secondary brain tumor). According to the National Cancer Institute, in 2013 the estimated new cases and deaths from brain tumor in the United States would be 23,130 and 14,080 respectively. There are many types of primary brain tumors. Primary brain tumors are named according to the type of cells or the part of the brain in which they originate. For example, most primary brain tumors begin in glial cells. This type of tumor is called a glioma. Among adults, the most common types are:

  • Meningioma: This tumor arises in the meninges. It’s usually benign (grade I) and grows slowly.
  • Oligodendroglioma: This tumor arises from cells that make the fatty substance that covers and protects nerves. It usually occurs in the cerebrum. It’s most common in middle-aged adults.
  • Astrocytoma: This tumor arises from star-shaped glial cells called astrocytes.

Among these, glioblastoma multiforme (GBM) is the most common and deadliest of malignant primary brain tumors in adults. Classified as a Grade IV (most serious) astrocytoma, GBM develops from the lineage of star-shaped glial cells, called astrocytes that support nerve cells. Even though GBM is one of the most aggressive forms of human cancers, the incident of this disease is fairly less.  Every year, in the United States approximately 7 out of 100,000 people are diagnosed with high-grade glioblastoma. Uncontrolled cellular proliferation, diffuse infiltration, and resistance to apoptosis are considered as hallmarks of GBM. The current standard of treatment in glioblastoma involves surgery followed by radiation therapy, and chemotherapy with the DNA alkylating agent temozolomide (TMZ).  The efficacy of this current treatment strategy is limited as the median survival is just over one year because of development of resistance. Therefore, more effective treatment plans need to be developed and explored. In a recent study published in the peer review journal Clinical Cancer Research (2013 Apr 25) Thorpe and colleagues reported that combined treatment of ataxia telangiectasia mutated (ATM) inhibitor and radiation significantly increased survival of mice bearing glioblastoma with p53 mutation compared to treatment with ATM inhibitor or radiation alone.

The nuclear protein kinase ataxia-telangiectasia mutated (ATM) plays a crucial role in DNA-damage response by transducing double-strand breaks. This kinase phosphorylates several effectors that play key roles in cell cycle progression and DNA repair pathways.

gLIOBLASYTOMA -resized-600 (1)

Ionizing radiation is the most effective therapy for glioblastoma. Ionizing radiation works by damaging the DNA of exposed tissue leading to cellular death. However, tumor cells evade death and contribute to radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. Therefore, combined treatment of ionizing radiation with inhibitors of DNA damage checkpoint may overcome the problem of resistance in glioblastoma. Since ATM is associated with DNA damage repair there are several small molecule ATM inhibitors that disrupt ATM function and enhances sensitivity of tumor cells to radiation as well as chemotherapeutic agents. ATM inhibitor KU-60019 is a potent inhibitor effectively blocking activation of key ATM targets and radiosensitizing human glioma cells in vitro. In their study Thorpe et al. (2013) showed that mice bearing glioblastoma survived longer periods of time (145 days) when treated with KU-60019 and radiation than mice treated with radiation alone (58 days) or KU-60019 alone (66 days). In addition, this study also noted that mice bearing glioma with mutant p53 are more sensitive to KU-60019 dependent radiosensitization than mice bearing glioma with p53 wild-type. Altogether this study suggests that ATM kinase inhibition may be an effective strategy as adjuvant therapy for patients with mutant p53 brain cancers.


1.Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006, 444(7120):756-760.

2.Biddlestone-Thorpe L, Sajjad M, Rosenberg E, Beckta JM, Valerie NC, Tokarz M, Adams BR, Wagner AF, Khalil A, Gilfor D et al: ATM kinase inhibition preferentially sensitizes p53 mutant glioma to ionizing radiation. Clin Cancer Res 2013.




Histone deacetylase (HDAC) inhibitors (HDIs), a new class of epigenetic anti-tumor agents, have shown promise so far in the treatment of hematologic malignancies. Many, if not most, cell lines tested in vitro show sensitivity to HDIs, and synergy in combinations is also often noted. Yet, Phase I and II trials of HDIs have uniformly been disappointing in solid tumors. Even preclinical models in which HDIs exhibited potent anti-tumor effects in vivo have not succeeded in the clinic. Therefore, a detailed understanding of the mechanisms of resistance to HDIs may lead to strategies designed to increase clinical efficacy. Studies have proposed several mechanisms of resistance which include increased expression of the P-glycoprotein (Pgp) encoding multidrug-resistance gene ABCB1, increased expressresistance to HDIS resized 600ion of reactive oxygen species (ROS) scavenger protein thioredoxin, elevated expression of anti-apoptotic proteins Bcl-2 and Bcl-xL, increased expression of histone HDAC enzymes, and activation of several signaling pathways including MAPK, phosphoinositide 3-kinase and signal transducer and activator of transcription.

The FDA approved histone deacetylase inhibitor romidepsin (istodax®) for the treatment of cutaneous T-cell lymphoma (CTCL) in 2009 and for the treatment of peripheral T-cell lymphoma (PTCL) in 2011. Disease progression was noted in some patients who initially responded to therapy, while disease in other patients did not respond to therapy suggesting that both de novo and acquired resistance to romidepsin were observed during the trial. Thus, studies are needed to determine the mechanisms of resistance to the HDI romidepsin particularly in T-cell lymphoma.

Several studies have noted selection of Pgp overexpression in vitro as a mechanism of drug resistance to romidepsin. The ease of selection of Pgp is in part because romidepsin is a substrate for Pgp, and in part based on ABCB1 gene induction as a consistent cellular response to HDIs. While induction of ABCB1 has been noted in normal and malignant peripheral blood mononuclear cells of patients treated with romidepsin, no evidence for Pgp-mediated resistance emerged in clinical samples obtained at the time of disease progression from patients with CTCL or PTCL. Therefore, identification of non-Pgp resistance mechanisms for romidepsin is warranted. A recent study published in the peer reviewed journal Blood by Chakraborty et al. (Blood. 2013 Mar 26) reported that activation of the mitogen activated protein kinase (MAPK) pathway conferred resistance to romidepsin through degradation of the pro-apoptotic BH-3 only protein Bim. To explore Pgp-independent mechanisms of resistance to romidpesin, a CTCL model consisting of the HuT78 cell line and its romidepsin-selected sublines were used. These sublines were separately selected in romidepsin in the presence of the Pgp-inhibitors verapamil or valspodar (PSC833) to avoid overexpression of Pgp. The resulting cell lines were resistant to romidepsin and inhibition of Pgp could reverse the resistance of only the cells that had not been selected in the presence of the Pgp inhibitors. The failure to reverse the resistance of the romidepsin-selected cells with a Pgp inhibitor suggested a different mechanism of action, which had not been identified in the earlier studies. A gene microarray study detected increased expression of the insulin receptor in the romidepsin-selected cells compared to the parental HuT78 cells. In addition, romidepsin-resistant cells also exhibited increased activation of MEK protein, a downstream component of the MAPK signaling pathway. Treating these resistant cells with the allosteric MEK inhibitors resulted in exquisite sensitivity while the parental HuT78 cells did not respond to the MEK inhibition. Restoration of the pro-apoptotic protein Bim was noted in romidepsin-resistant cells following MEK inhibition which was otherwise found to be degraded in the resistant cells. Combined treatment of MEK inhibitor with romidepsin also caused increased death of resistant cells. In their study, Chakraborty and colleagues also noted loss of Bim in the skin biopsy samples obtained from CTCL patients who experienced disease progression after romidepsin treatment. In addition, this study also reported perturbation of the MAPK regulated genes in the CTCL patients treated with romidepsin. Collectively these observations suggested that activation of the MAPK pathway may limit efficacy of the HDI romidepsin through degradation of the pro-apoptotic protein Bim, and in future clinical trials combination of romidepsin with MEK inhibitor may exhibit promising results.



1.Fantin VR, Richon VM. Mechanisms of resistance to histone deacetylase inhibitors and their therapeutic implications. Clin Cancer Res. 2007;13(24):7237-7242.

2.Chakraborty AR, Robey RW, Luchenko VL, et al. MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with a MEK inhibitor. Blood. 2013.

The Hippo-YAP Pathway: New Connection between Cancer and Stem Cells.

First discovered  by laboratories studying  Drosophila development 18 years ago1-3, the Hippo-YAP signaling pathway (also known as the Salvador-Warts-Hippo Pathway) is a novel pathway implicated in organism development, stem cell biology, and cancer biology4. While not much is known about the Hippo-YAP pathway, this signaling mechanism could lead to a promising paradigm in regenerative medicine and treating cancer.

While we are far from fully discovering every aspect Hippo-YAP signaling pathway, some components of this novel pathway have been uncovered. In mammalian cells, the first signal modulator to be stimulated is mammalian STE-20 protein kinase 1 & 2(Mst1/2). This stimulation causes autophosphorylation, which in turn starts a kinase cascade; phosphorylating the proteins Salvador homolog 1 (Sav1), MOB kinase activator 1 (Mob1), and large tumor suppressor 1 & 2 (Lats1/2). Once Lats1/2 is activated, it phosphorylates YAP (Yes-associated protein)4. This phosphorylation of YAP sequesters it outside of the cell and leads to its proteosomal degradation and thus blocking its ability to complex with the protumor TEAD transcription factors, which in turn inhibits proliferation and blocks inhibition of apoptosis4. Interestingly, other alternative mechanisms, such as directly targeting YAP via the WNT pathway, or activation of YAP/TAZ via the SMAD signaling pathway by TGFβ and BMP, have been demonstrated5. While the stimulation of the Hippo pathway is still being revealed, researchers have discovered two mechanisms hippo stimulation: cell-cell contact and activation of G-protein coupled receptors4,5.  Stimulation of G-protein Coupled Receptors (GPCRs), Go with the ligands LPA or S1P and Gs with glucagon and epinephrine, have been shown to activate the Hippo-YAP signaling pathway, causing phosphorylation of Mst1/26. On the other hand, the cell-cell contact method of hippo activation most likely phosphorylates Mst1/2 through the upstream component: Merlin6.  However, while there is phosphorylation of Mst1/2 in both stimulation methods, neither stimulation pathway is known, save one or two components, upstream of Mst1/2. Furthermore, the complexity of this signaling pathway is certain and upstream signals may be redundant6.

The Hippo-YAP signaling pathway plays a crucial role in embryological development. At the middle of this is the Hippo signaling component is transcriptional co-activator with PDZ-binding motif (TAZ, also known as WWTR1). TAZ is able to regulate the signaling mechanisms of the SMAD2/3-4 signaling pathway4; a pathway that regulates the TGF-beta signaling cascade that is important in early embryogenesis7. Furthermore, it has been demonstrated that functional loss of the TAZ protein, and not YAP, will lead to uncontrolled differentiation of human embryonic stem cells (hESCs) as well as loss of self-renewal of hESCs4.  Surprisingly, although YAP is not as important as TAZ to block differentiation, YAP is inactivated during normal hESC differentiation4. In addition to stem cell differentiation, the Hippo-YAP signaling pathway has been shown to be important for polarization of tissues8 in both planar and apicobasal cell polarity5, tissue shape and patterning9, and overall tissue homeostasis9.

While the activation of the Hippo-YAP pathway seems to be important for embryogenesis, the dysregulation of the Hippo-YAP pathway seems to play a striking role in tumorigenesis9. Deletion of the upstream Mst1/2 component of the Hippo-YAP pathway has been shown to cause uncontrolled liver growth. Microscopic analysis of liver biopsies revealed that these tissues were full of hepatocellular carcinoma and cholangiocarcinoma4. Likewise, overactivation of the YAP protein caused uncontrolled, extreme thickening of epidermal layer4. However, the pathway that is thought to be involved in this process of YAP activation is not the canonical Hippo-YAP pathway, but a signaling through alpha catenin. The catenin family and the Hippo-YAP signaling pathway were further shown to interact when overexpression of YAP facilitated the expression of Notch/Wnt signaling pathway indirectly by YAP-driven overexpression of beta catenin4. Because the Notch/Wnt pathways are important for cancer stem cell phenotype10 and cancer metastasis11, further investigation into the roles of the Hippo-YAP signaling pathway could bring a lot of clinical significance.

describe the imageAt the writing of this blog, no proposed drug has been proposed that directly targets the Hippo signaling pathway.  However, many possible targets for therapy are being investigated that would also affect the Hippo signaling pathway5. One of these is targeting the homeodomain-interacting protein kinase 2 (HIPK2) which has been demonstrated to activate YAP 5.In addition, using GPCR antagonists, such as Dobutamine, have been shown to decrease activation levels of YAP5. Also promising, researchers have solved many domains of the YAP structure, which may lead to specific inhibition of this oncogene by potential inhibitors12. Because of the role that the Hippo signaling pathway may play on tumor growth inhibition, it may not be long before candidate drugs targeting this pathway will start to enter the FDA drug pipeline.


Further Reading:

1              Justice, R. W., Zilian, O., Woods, D. F., Noll, M. & Bryant, P. J. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes & development 9, 534-546 (1995).

2              Xu, T., Wang, W., Zhang, S., Stewart, R. A. & Yu, W. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053-1063 (1995).

3              Wu, S., Huang, J., Dong, J. & Pan, D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114, 445-456 (2003).

4              Ramos, A. & Camargo, F. D. The Hippo signaling pathway and stem cell biology. Trends in cell biology 22, 339-346, doi:10.1016/j.tcb.2012.04.006 (2012).

5              Harvey, K. F., Zhang, X. & Thomas, D. M. The Hippo pathway and human cancer. Nature reviews. Cancer 13, 246-257, doi:10.1038/nrc3458 (2013).

6              Yu, F. X. et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150, 780-791, doi:10.1016/j.cell.2012.06.037 (2012).

7              Massague, J. TGFbeta signalling in context. Nature reviews. Molecular cell biology 13, 616-630, doi:10.1038/nrm3434 (2012).

8              Yu, F. X. & Guan, K. L. The Hippo pathway: regulators and regulations. Genes & development 27, 355-371, doi:10.1101/gad.210773.112 (2013).

9              Pan, D. The hippo signaling pathway in development and cancer. Developmental cell 19, 491-505, doi:10.1016/j.devcel.2010.09.011 (2010).

10           Takebe, N., Harris, P. J., Warren, R. Q. & Ivy, S. P. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nature reviews. Clinical oncology 8, 97-106, doi:10.1038/nrclinonc.2010.196 (2011).

11           Fodde, R. & Brabletz, T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Current opinion in cell biology 19, 150-158, doi:10.1016/ (2007).

12           Sudol, M., Shields, D. C. & Farooq, A. Structures of YAP protein domains reveal promising targets for development of new cancer drugs. Seminars in cell & developmental biology 23, 827-833, doi:10.1016/j.semcdb.2012.05.002 (2012).