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Featured researches published by Chaitanya Churi.


Oncologist | 2014

New Routes to Targeted Therapy of Intrahepatic Cholangiocarcinomas Revealed by Next-Generation Sequencing

Jeffrey S. Ross; Kai Wang; Rami N. Al-Rohil; Janne V. Rand; David M. Jones; Hwa J. Lee; Christine E. Sheehan; Geoff Otto; Gary A. Palmer; Roman Yelensky; Doron Lipson; Deborah Morosini; Matthew J. Hawryluk; Daniel V.T. Catenacci; Vincent A. Miller; Chaitanya Churi; Siraj M. Ali; Philip J. Stephens

BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer that is rarely curable by surgery and is rapidly increasing in incidence. Relapsed ICC has a poor prognosis, and current systemic nontargeted therapies are commonly extrapolated from those used in other gastrointestinal malignancies. We hypothesized that genomic profiling of clinical ICC samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized approach to therapy. METHODS DNA sequencing of hybridization-captured libraries was performed for 3,320 exons of 182 cancer-related genes and 36 introns of 14 genes frequently rearranged in cancer. Sample DNA was isolated from 40 μm of 28 formalin-fixed paraffin-embedded ICC specimens and sequenced to high coverage. RESULTS The most commonly observed alterations were within ARID1A (36%), IDH1/2 (36%), and TP53 (36%) as well as amplification of MCL1 (21%). Twenty cases (71%) harbored at least one potentially actionable alteration, including FGFR2 (14%), KRAS (11%), PTEN (11%), CDKN2A (7%), CDK6 (7%), ERBB3 (7%), MET (7%), NRAS (7%), BRCA1 (4%), BRCA2 (4%), NF1 (4%), PIK3CA (4%), PTCH1 (4%), and TSC1 (4%). Four (14%) of the ICC cases featured novel gene fusions involving the tyrosine kinases FGFR2 and NTRK1 (FGFR2-KIAA1598, FGFR2-BICC1, FGFR2-TACC3, and RABGAP1L-NTRK1). CONCLUSION Two thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for to individual patients.


PLOS ONE | 2014

Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications

Chaitanya Churi; Rachna T. Shroff; Ying Wang; Asif Rashid; Hyunseon C. Kang; Jacqueline Weatherly; Mingxin Zuo; Ralph Zinner; David S. Hong; Funda Meric-Bernstam; Filip Janku; Christopher H. Crane; Lopa Mishra; J.N. Vauthey; Robert A. Wolff; Gordon B. Mills; Milind Javle

Background Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics. Methods We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials. Results There were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors. Conclusion There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.


Journal of Hematology & Oncology | 2015

HER2/neu-directed therapy for biliary tract cancer

Milind Javle; Chaitanya Churi; Hyunseon C. Kang; Rachna T. Shroff; Filip Janku; Rakesh Surapaneni; Mingxin Zuo; Christian Barrera; Humaid O. Al-Shamsi; Sunil Krishnan; Lopa Mishra; Robert A. Wolff; Ahmed Kaseb; Melanie B. Thomas; Abby B. Siegel

BackgroundBiliary cancers are highly aggressive tumors that are often diagnosed an advanced disease stage and have a poor outcome with systemic therapy. Recent efforts towards molecular characterization have identified a subset of biliary patients that have HER2/neu amplification or mutation. HER2/neu amplification is associated with response to HER2/neu-directed therapy in breast and gastric cancers. However, the efficacy of HER2/neu-targeted therapy in biliary cancers is unknown.Patients and methodsWe retrospectively reviewed cases of advanced gallbladder cancer and cholangiocarcinoma with HER2/neu genetic aberrations or protein overexpression who received HER2/neu-directed therapy between 2007 and 2014. Clinical data were retrieved from medical records, and imaging studies were independently reviewed.ResultsNine patients with gallbladder cancer and five patients with cholangiocarcinoma had received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab) during the study period. In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in eight cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu-directed therapy. One patient had HER2/neu mutation and experienced a mixed response after lapatinib therapy. The duration of response varied from 8+ to 168 weeks (median 40 weeks), and three patients are still on therapy. One patient developed HER2/neu amplification as a secondary event after FGFR-directed therapy for FGF3-TACC3 gene fusion. The cholangiocarcinoma cases treated in this series had a higher proportion of HER2/neu mutations, and no radiological responses were seen in these patients despite HER2/neu-directed therapy.ConclusionsHER2/neu blockade is a promising treatment strategy for gallbladder cancer patients with gene amplification and deserves further exploration in a multi-center study.


Human Pathology | 2014

Molecular Characterization of Gallbladder Cancer using Somatic Mutation Profiling

Milind Javle; Asif Rashid; Chaitanya Churi; Siddhartha Kar; Mingxin Zuo; Agda Karina Eterovic; Graciela M. Nogueras-Gonzalez; Filip Janku; Rachna T. Shroff; Thomas A. Aloia; Jean Nicolas Vauthey; Steven A. Curley; Gordon B. Mills; Iván Roa

Gallbladder cancer is relatively uncommon with high incidence in certain geographic locations, including Latin America, East and South Asia and Eastern Europe. Molecular characterization of this disease has been limited and targeted therapy options for advanced disease remain an open area of investigation. In the present study, surgical pathology obtained from resected gallbladder cancer cases (n=72) was examined for the presence of targetable, somatic mutations. All cases were formalin-fixed and paraffin-embedded (FFPE). Two approaches were used: a) mass spectroscopy-based profiling for 159 point (‘hot-spot’) mutations in 33 genes commonly involved in solid tumors and b) next-generation sequencing (NGS) platform that examined the complete coding sequence of in 182 cancer-related genes. Fifty-seven cases were analyzed for hotspot mutations and 15 for NGS. Fourteen hotspot mutations were identified in nine cases. Of these, KRAS mutation was significantly associated with poor survival on multivariate analysis. Other targetable mutations included PIK3CA (N=2) and ALK (N=1). On NGS, 26 mutations were noted in 15 cases. P53 and PI3 kinase pathway (STK11, RICTOR,TSC2) mutations were common. One case had FGF10 amplification while another had FGF3-TACC gene fusion, not previously described in gallbladder cancer. In conclusion, somatic mutation profiling using archival FFPE samples from gallbladder cancer is feasible. NGS, in particular may be a useful platform for identifying novel mutations for targeted therapy.


British Journal of Cancer | 2015

Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer.

M. Zuo; Asif Rashid; Chaitanya Churi; Jean Nicolas Vauthey; Ping Chang; Yanan Li; Mien Chie Hung; D. Li; Milind Javle

Background:Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs).Methods:Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs.Results:Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA-1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment.Conclusions:Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy.


Molecular Cancer Therapeutics | 2013

Abstract B132: Next generation sequencing yields promising targets in advanced cholangiocarcinoma (CCA).

Chaitanya Churi; Asif Rashid; Rachna T. Shroff; Lopa Mishra; Mingxin Zuo; Ahmed Kaseb; Filip Janku; Thomas A. Aloia; J.N. Vauthey; Steven A. Curley; Siraj M. Ali; Gary A. Palmer; Milind Javle

Background: The incidence of CCA is rising and the clinical efficacy of systemic therapy is suboptimal. Next generation sequencing (NGS) technology offers potential for targeted therapeutics against genetically heterogenous solid tumors including cholangiocarcinoma (CCA). Methods: DNA was extracted from biopsy specimens of 56 patients of CCA seen at MD Anderson Cancer Center Houston, TX. DNA sequencing was performed for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform.Results: 162 genomic variations (GV) were identified from 56 patient samples with an average of 2.89 GVs/patient (range 0-10). GVs identified were mutations (72%), amplifications (17%), loss/deletions (7%) and others (4%). 6 (11%) tumors showed no GVs. Most frequent GVs were TP53 (35%), KRAS (31%), ARID1A (16%), PBRM1 (11%), BAP1 (9%), ERBB2 (9%), FBXW7 (9%), SMAD4 (9%) and IDH1 (7%). ERBB2 GVs included 4 mutations and 1 amplification. KRAS mutation was associated with a statistically significant reduction in overall survival (OS). Mean OS in patients with KRAS mutation was 32 weeks vs. 63 weeks in KRAS wt (t = -2.126, p = 0.039). Ingenuity Pathway Analysis indicated disruption in cell cycle, proliferation, development, death and DNA repair pathways. Targetable signaling pathways from this study are described in Table 1. Targetable GVs were noted in 59% of patients. These are potentially targetable by inhibitors to ERBB2, FGF, mTOR, MEK, BRAF and PARP-1. Conclusion: These data are the single largest compilation of NGS analysis on CCA patients and demonstrate the range of GVs that are eligible for investigational targeted therapies. These results can be used as a basis to develop personalized treatments for CCA patients based on individual genetic profiles. ![Figure][1] Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B132. Citation Format: Chaitanya R. Churi, Asif Rashid, Rachna Shroff, Lopa Mishra, Mingxin Zuo, Ahmed Kaseb, Filip Janku, Thomas A. Aloia, Jean-Nicholas Vauthey, Steven Curley, Siraj Ali, Gary Palmer, Milind Javle. Next generation sequencing yields promising targets in advanced cholangiocarcinoma (CCA). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B132. [1]: pending:yes


Molecular Cancer Therapeutics | 2013

Abstract C171: Novel therapeutic strategies targeting the hedgehog signaling pathway and mTOR pathway in biliary tract cancer (BTC).

Mingxin Zuo; Asif Rashid; Chaitanya Churi; Mien-Chie Hung; Milind Javle

Background: BTC represents the second most common primary cancer of the hepatobiliary system and is associated with a poor prognosis. Activation of PI3K/mTOR and hedgehog pathways has been demonstrated in biliary cancer. Activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenesis through S6K1-mediated Gli phosphorylation. Recently, synergistic antitumor efficacy was demonstrated with the combination of hedgehog and mTOR inhibitors, particularly in cases with mTOR/S6K pathway in esophageal cancer (Cancer Cell 2012; 21(3):374-87). Methods: Gene expression profiling was performed on 10 human biliary tract cancer cell lines (MMNK-1, Mz-ChA-1, Sk-ChA-1, KKU-M213, KKU-M214, KKU-M055, KKU-M139, M213L5H, and M213LOH) by real-time qRT-PCR. CellTiter-Glo® luminescent cell viability assay, colony formation, and stem cells morphology spheres were conducted to examine the effects of the combination of Rapamycin and Vismodegib on cell proliferation. Western-blot assay was used to examine the related protein expression. Fluorescence-activated cell sorting (FACS) was used to examine the effects of the combination on BTC stem cells. Results: Based on Gli1 and S6K gene expression, the Mz-ChA-1 and Sk-ChA-1 cell lines were chosen to investigate the effects of the combination of Rapamycin and Vismodegib on BTC (Table 1). Combination of Rapamycin and Vismodegib exhibited the synergistic antiproliferative effect on Mz-ChA-1 cells. The combination of Rapamycin and Vismodegib inhibited the Mz-ChA-1 cell proliferation, colony formation and stem cell sphere formation. This combination therapy decreases the NANOG, OTC3/4, and E-Cadherin gene expression in Mz-ChA-1 stem cells. Furthermore, the drug combination can decrease the phospho-p70S6K and Gli1 protein and increase cleaved caspase-3 expression in Mz-ChA-1 cells. No such effect was observed in Sk-ChA-1 cells.Conclusions: Crosstalk between the mTOR pathway and HH pathway provides a new avenue for combination therapy in BTC with hedgehog and mTOR inhibitors. ![Figure][1] Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C171. Citation Format: Mingxin Zuo, Asif Rashid, Chaitanya Churi, Mien-Chie Hung, Milind Javle. Novel therapeutic strategies targeting the hedgehog signaling pathway and mTOR pathway in biliary tract cancer (BTC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C171. [1]: pending:yes


Journal of Clinical Oncology | 2013

Comparison of microRNA (MiRNA) expression profiles between opisthorchis viverrini-associated cholangiocarcinoma (OV-CCA) and non-opisthorchis viverrini-associated cholangiocarcinoma (non-OV CCA).

Suebpong Tanasanvimon; Asif Rashid; Sopit Wongkham; Chaitanya Churi; Zhimin Tong; David R. Fogelman; Atit Silsirivanit; Boris Blechacz; Naruemon Klaikaew; Vajarabhongsa Bhudhisawasdi; Jean Nicolas Vauthey; Milind Javle

206 Background: Cholangiocarcinoma in Thailand and Laos is associated with the liver fluke Opisthorchis viverrini (OV). Molecular differences between OV-CCA and Non-OV CCA remain to be defined. MiRNAs are regulators of mRNA that result in transcriptional repression or gene silencing. MiRNA profiles of OV vs. non-OV CCA have not yet been studied. Methods: 50 OV-CCA and 16 non-OV CCA pathological samples were obtained from Liver Fluke and Cholangiocarcinoma Center, Khonkaen University, Thailand and University of Texas, MD Anderson Cancer Center (MDACC), USA, respectively. Macrodissected common bile duct samples from MDACC were used as control groups. Global miRNA expression profiling was performed using the miRCURY LNA microRNA Array (Exiqon).qRT-PCR and in situ hybridization (ISH) were used to validate the miRNAs noted to be significant on the microRNA array. Results: Ten samples of OV and non-OV CCA were analyzed for global miRNA expression; 46 were used for validation. MiRNA microarray identified 71 miRN...


Gastrointestinal cancer research : GCR | 2014

Overexpression of the HER2/neu Gene: A New Therapeutic Possibility for Patients With Advanced Gallbladder Cancer.

Iván Roa; Gonzalo de Toro; Kurt A. Schalper; Xabier De Aretxabala; Chaitanya Churi; Milind Javle


Journal of Clinical Oncology | 2015

BAP1 mutation-associated cholangiocarcinoma: An aggressive disease.

Deepa Anand; Chaitanya Churi; Asif Rashid; Rachna T. Shroff; Mingxin Zuo; Claudius Conrad; Jean Nicolas Vauthey; Milind Javle

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Milind Javle

University of Texas MD Anderson Cancer Center

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Asif Rashid

University of Texas MD Anderson Cancer Center

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Mingxin Zuo

University of Texas MD Anderson Cancer Center

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Rachna T. Shroff

University of Texas MD Anderson Cancer Center

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Filip Janku

University of Texas MD Anderson Cancer Center

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Jean Nicolas Vauthey

University of Texas MD Anderson Cancer Center

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Lopa Mishra

George Washington University

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Ahmed Kaseb

University of Texas MD Anderson Cancer Center

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Steven A. Curley

University of Texas MD Anderson Cancer Center

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Thomas A. Aloia

University of Texas MD Anderson Cancer Center

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