Rethinking gamma-secretase inhibitors for treatment of non-small cell lung cancer: Is Notch the target?
Abstract Lung cancer is the leading cause of cancer deaths among men and women. Gamma-secretase inhibitors, a class of small molecule compounds that target the Notch pathway, have been tested to treat non-small cell lung cancer (NSCLC) in pre-clinical and clinical trials. Although ɣ-secretase inhibitors elicit a response in some tumors as single agents and sensitize NSCLC to cytotoxic and targeted therapies, they have not yet been approved for NSCLC therapy. We discuss our recently published pre-clinical study using the ɣ-secretase inhibitor AL101, formerly BMS906024, on cell lines and PDX models of NSCLC, prima...
Source: Clinical Cancer Research - August 13, 2018 Category: Cancer & Oncology Authors: Pine SR Tags: Clin Cancer Res Source Type: research

A PHASE I/IIa TRIAL USING CD19-TARGETED THIRD GENERATION CAR T CELLS FOR LYMPHOMA AND LEUKEMIA.
CONCLUSIONS: Third generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre and post treatment can be used to find response biomarkers. PMID: 30097433 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 10, 2018 Category: Cancer & Oncology Authors: Enblad G, Karlsson H, Gammelgard G, Wenthe J, Lovgren T, Amini RM, Wikstrom KI, Essand M, Savoldo B, Hallbook H, Höglund M, Dotti G, Brenner MK, Hagberg H, Loskog A Tags: Clin Cancer Res Source Type: research

A phase I trial of a guadecitabine (SGI-110) and irinotecan in metastatic colorectal cancer patients previously exposed to irinotecan.
CONCLUSIONS: We report the first study of chemo-priming with epigenetic therapy in GI cancers. Guadecitabine 45 mg/m2 and irinotecan 125mg/m2 with GFS was safe and tolerable in mCRC patients, with early indication of benefit. These data have provided the basis for an ongoing phase II randomized, multicenter trial. PMID: 30097434 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 10, 2018 Category: Cancer & Oncology Authors: Lee V, Wang JS, Zahurak ML, Gootjes EC, Verheul HMW, Parkinson RM, Kerner Z, Sharma A, Rosner GL, De Jesus-Acosta A, Laheru DA, Le DT, Oganesian A, Lilly-Foreman E, Brown T, Jones PA, Baylin SB, Ahuja N, Azad NA Tags: Clin Cancer Res Source Type: research

Loss of nuclear localized Parathyroid Hormone-related Protein in primary breast cancer predicts poor clinical outcome and correlates with suppressed Stat5 signaling.
CONCLUSIONS: This study overturns the prevailing view that PTHrP is upregulated in primary breast cancers and identifies a direct prolactin-Stat5-PTHrP axis that is progressively lost in more aggressive tumors. PMID: 30097435 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 10, 2018 Category: Cancer & Oncology Authors: Tran TH, Utama FE, Sato T, Peck AR, Langenheim JF, Udhane SS, Sun Y, Liu C, Girondo MA, Kovatich AJ, Hooke JA, Shriver CD, Hu H, Palazzo J, Bibbo M, Auer PL, Flister MJ, Hyslop TM, Mitchell EP, Chervoneva I, Rui H Tags: Clin Cancer Res Source Type: research

Rates of ERBB2 Alterations Across Melanoma Subtypes and a Complete Response to Trastuzumab Emtansine in an ERBB2-amplified Acral Melanoma.
CONCLUSIONS: ERBB2 amplification is present in a minority of acral lentiginous and mucosal melanomas. Activating mutations in ERBB2 were identified in non-uveal melanoma subtypes and are frequently co-mutated with canonical drivers. HER2 could represent a therapeutically relevant target across melanoma subtypes. PMID: 30093446 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 9, 2018 Category: Cancer & Oncology Authors: Gottesdiener LS, O'Connor S, Busam KJ, Won H, Solit DB, Hyman DM, Shoushtari AN Tags: Clin Cancer Res Source Type: research

Ultrahigh dose-rate radiotherapy: Next steps for FLASH-RT.
Abstract A new way of delivering radiotherapy at very high dose-rates is described and compared to conventional radiotherapy. The ultrahigh dose-rate therapy reduces damage to normal pig skin and exerts potent activity against spontaneous nasal tumours in cat patients. The implications for clinical development of this approach are discussed. PMID: 30093447 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 9, 2018 Category: Cancer & Oncology Authors: Harrington KJ Tags: Clin Cancer Res Source Type: research

Role of the RANK/RANKL Pathway in Multiple Myeloma.
This article will review currently available evidence supporting a role for RANK/RANKL signaling in tumorigenesis, with a focus on patients with multiple myeloma. PMID: 30093448 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 9, 2018 Category: Cancer & Oncology Authors: Raje NS, Bhatta S, Terpos E Tags: Clin Cancer Res Source Type: research

Phase 2 Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma.
CONCLUSION: This combination shows antitumor activity, particularly in patients with MYCN non-amplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent. PMID: 30093449 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 9, 2018 Category: Cancer & Oncology Authors: Dubois SG, Mosse YP, Fox E, Kudgus RA, Reid JM, McGovern R, Groshen S, Bagatell R, Maris JM, Twist CJ, Goldsmith KC, Granger M, Weiss B, Park JR, Macy ME, Cohn SL, Yanik GA, Wagner LM, Hawkins R, Courtier J, Lai H, Goodarzian F, Shimada H, Boucher N, Czar Tags: Clin Cancer Res Source Type: research

Single Cell Analyses of Prostate Cancer Liquid Biopsies Acquired by Apheresis.
CONCLUSION/DISCUSSION: Apheresis facilitated the capture of large numbers of CTCs non-invasively with minimal morbidity and allowed the deconvolution of intra-patient heterogeneity and clonal evolution. PMID: 30093450 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 9, 2018 Category: Cancer & Oncology Authors: Lambros MB, Seed G, Sumanasuriya S, Gil V, Crespo M, Fontes MS, Chandler R, Mehra N, Fowler G, Ebbs B, Flohr PR, Miranda S, Yuan W, Mackay A, Ferreira A, Pereira R, Bertan C, Figueiredo I, Riisnaes R, Nava Rodrigues D, Sharp A, Goodall J, Boysen G, Carrei Tags: Clin Cancer Res Source Type: research

Identification of Tissue Specific DNA Methylation Signatures for Thyroid Nodule Diagnostics.
CONCLUSIONS: These data show that epigenetic testing can provide outstanding diagnostic accuracy for thyroid nodules. PMID: 30093451 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 9, 2018 Category: Cancer & Oncology Authors: Yim JH, Choi AH, Li AX, Qin H, Chang S, Tong ST, Chu P, Kim BW, Schmolze D, Lew R, Ibrahim Y, Poroyko VA, Salvatierra S, Baker A, Wang J, Wu X, Pfeifer GP, Fong Y, Hahn MA Tags: Clin Cancer Res Source Type: research

Targeting the CDK4/6-Rb pathway enhances response to PI3K inhibition in PIK3CA mutant lung squamous cell carcinoma.
Abstract PURPOSE: Lung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancer characterized by multiple genetic alterations, particularly PI3K pathway alterations which have been identified in over 50% of LUSC cases. Despite being an attractive target, single agent PI3K inhibitors have demonstrated modest response in LUSC. Thus, novel combination therapies targeting LUSC are needed. EXPERIMENTAL DESIGN: PI3K inhibitors alone and in combination with CDK4/6 inhibitors were evaluated in previously established LUSC patient-derived xenografts (PDX) using an in vivo screening method. Screen...
Source: Clinical Cancer Research - August 9, 2018 Category: Cancer & Oncology Authors: Shi R, Li M, Raghavan V, Tam S, Cabanero M, Pham NA, Shepherd FA, Moghal N, Tsao MS Tags: Clin Cancer Res Source Type: research

Intratumoral G100, a TLR4 agonist, induces anti-tumor immune responses and tumor regression in patients with Merkel cell carcinoma.
CONCLUSIONS: In this first-in-human study, IT G100 induced anti-tumor immune responses, demonstrated acceptable safety, and showed encouraging clinical activity. PMID: 30093453 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 9, 2018 Category: Cancer & Oncology Authors: Bhatia S, Miller NJ, Lu H, Vandeven NV, Ibrani D, Shinohara M, Byrd D, Parvathaneni U, Kulikauskas RM, Ter Meulen J, Hsu FJ, Koelle DM, Nghiem P Tags: Clin Cancer Res Source Type: research

Early reduction in ctDNA predicts survival in lung and bladder cancer patients treated with durvalumab.
CONCLUSIONS: ctDNA VAF changes are strongly correlated with duration of treatment, antitumor activity and clinical outcomes in NSCLC and UC. Early on-treatment reduction in ctDNA VAF may be a useful predictor of long-term benefit from immunotherapy. Prospective studies should validate these findings and the value of utilizing early changes in ctDNA for therapeutic decision-making by identifying non-responders to checkpoint inhibitor monotherapies and guiding combination therapies. PMID: 30093454 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 9, 2018 Category: Cancer & Oncology Authors: Raja R, Kuziora M, Brohawn P, Higgs BW, Gupta A, Dennis PA, Ranade K Tags: Clin Cancer Res Source Type: research

BMI1 drives metastasis of prostate cancer in Caucasian and African-American men and is a potential therapeutic target: hypothesis tested in race-specific models.
CONCLUSION: BMI1, a major driver of metastasis, represents a promising therapeutic target for treating advanced CaP in patients (including those belonging to high-risk group). PMID: 30087142 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 7, 2018 Category: Cancer & Oncology Authors: Ganaie A, Beigh FH, Astone M, Ferrari MG, Maqbool R, Umbreen S, Parray AS, Siddique HR, Hussain T, Murugan P, Morrissey C, Koochekpour S, Deng Y, Konety BR, Hoeppner LH, Saleem M Tags: Clin Cancer Res Source Type: research

Subjugation of TGF β Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End-Joining.
CONCLUSIONS: HPV-positive HNSCC cells are unresponsive to TGFβ. Abrogated TGFβ signaling compromises homologous recombination and shifts reliance on alt-EJ repair that provides a mechanistic basis for sensitivity to PARP inhibitors. The effect of HPV in HNSCC provides critical validation of TGFβ's role in DNA repair proficiency and further raises the translational potential of TGFβ inhibitors in cancer therapy. PMID: 30087144 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 7, 2018 Category: Cancer & Oncology Authors: Liu Q, Ma L, Jones T, Palomero L, Pujana MA, Martinez-Ruiz H, Ha PK, Murnane J, Cuartas I, Seoane J, Baumann M, Linge A, Barcellos-Hoff MH Tags: Clin Cancer Res Source Type: research

Loss of Function of Canonical Notch Signaling Drives Head and Neck Carcinogenesis.
CONCLUSIONS: These findings inform on the contribution of loss of canonical Notch signaling in head and neck carcinogenesis. PMID: 30087145 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 7, 2018 Category: Cancer & Oncology Authors: Nyman P, Buehler D, Lambert PF Tags: Clin Cancer Res Source Type: research

Family history of breast or prostate cancer and prostate cancer risk.
CONCLUSIONS: Our study found that men with a family history of breast or prostate cancer had elevated prostate cancer risks, including risk of lethal disease. These findings have translational relevance for cancer risk prediction in men. PMID: 30082473 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 6, 2018 Category: Cancer & Oncology Authors: Barber LE, Gerke T, Markt SC, Peisch SF, Wilson KM, Ahearn TU, Giovannucci EL, Parmigiani G, Mucci LA Tags: Clin Cancer Res Source Type: research

Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non-Small Cell Lung Cancer: A Phase 1b Study.
CONCLUSIONS: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies. PMID: 30082474 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 6, 2018 Category: Cancer & Oncology Authors: Kim ES, Kelly K, Paz-Ares L, Garrido P, Jalal S, Mahadevan D, Guttierrez MA, Provencio M, Schaefer E, Shaheen M, Johnston EL, Turner PK, Kambhampati SRP, Beckmann R, Hossain A, John WJ, Goldman JW Tags: Clin Cancer Res Source Type: research

Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/vincristine in Relapsed/refractory Aggressive B-cell Lymphoma.
CONCLUSIONS: The combination of alisertib 50 mg BID plus rituximab or alisertib 40 mg BID plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL. PMID: 30082475 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 6, 2018 Category: Cancer & Oncology Authors: Kelly KR, Friedberg JW, Park SI, McDonagh KT, Hayslip J, Persky D, Ruan J, Puvvada S, Rosen PJ, Padmanabhan Iyer S, Stefanovic A, Bernstein SH, Weitman S, Karnad AB, Monohan G, VanderWalde A, Mena R, Schmelz M, Spier C, Groshen S, Venkatakrishnan K, Zhou Tags: Clin Cancer Res Source Type: research

Circulating biomarkers and resistance to endocrine therapy in metastatic breast cancers: correlative results from AZD9496 oral SERD Phase I trial.
n EA, Barrett JC, Baird RD, Hayes DF Abstract BACKGROUND: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER) positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERDs). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) were explored as potential non-invasive tools, alongside paired tumor biopsies, to assess pharmacodynami...
Source: Clinical Cancer Research - August 6, 2018 Category: Cancer & Oncology Authors: Paoletti C, Schiavon G, Dolce EM, Darga EP, Carr TH, Geradts J, Hoch M, Klinowska T, Lindemann JPO, Marshall G, Morgan S, Patel P, Rowlands V, Sathiyayogan N, Aung K, Hamilton EP, Patel MR, Armstrong AC, Jhaveri K, Im SA, Iqbal N, Butt F, Dive C, Harringt Tags: Clin Cancer Res Source Type: research

A visually apparent and quantifiable CT imaging feature identifies biophysical subtypes of pancreatic ductal adenocarcinoma.
CONCLUSION: At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease. PMID: 30082477 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 6, 2018 Category: Cancer & Oncology Authors: Koay EJ, Lee Y, Cristini V, Lowengrub JS, Kang Y, San Lucas FA, Hobbs BP, Ye R, Elganainy D, Almahariq M, Amer AM, Yu S, Chatterjee D, Yan H, Park PC, Rios Perez MV, Li D, Garg N, Reiss K, Chauhan A, Zaid MM, Nikzad N, Wolff RA, Javle M, Varadhachary GR, Tags: Clin Cancer Res Source Type: research

Endoglin targeting in colorectal tumor microenvironment.
Abstract On endothelial cells, the TGFβ/BMP-9 co-receptor endoglin emerged as a promising anti-angiogenic target in colorectal cancer (CRC). Its promiscuous expression in cancer associated fibroblasts (CAFs) emerges to facilitate metastasis. The multi-target impact of neutralizing endoglin may offer added benefit in controlling CRC. PMID: 30076135 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 3, 2018 Category: Cancer & Oncology Authors: Becker LM, LeBleu VS Tags: Clin Cancer Res Source Type: research

Pericytes elicit resistance to vemurafenib and sorafenib therapy in thyroid carcinoma via the TSP-1/TGF β1 axis.
CONCLUSIONS: Pericytes shield BRAFV600E-PTC cells from targeted therapy via TSP-1 and TGFβ1, suggesting this axis as a new therapeutic target for overcoming resistance to BRAFV600E and TK inhibitors. PMID: 30076136 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 3, 2018 Category: Cancer & Oncology Authors: Prete A, Lo AS, Sadow PM, Bhasin SS, Antonello ZA, Vodopivec DM, Ullas S, Sims JN, Clohessy JG, Dvorak AM, Sciuto T, Bhasin M, Murphy-Ullrich JE, Lawler J, Karumanchi SA, Nucera C Tags: Clin Cancer Res Source Type: research

Local phototherapy synergizes with immunoadjuvant for treatment of pancreatic cancer through induced immunogenic tumor vaccine.
CONCLUSIONS: This study indicated that combination of local phototherapy and immunotherapy induced a systemic immunity against established tumors and metastases in an aggressive, preclinical pancreatic tumor model, leading to a potential clinical method for patients with advanced pancreatic cancer. PMID: 30068705 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 1, 2018 Category: Cancer & Oncology Authors: Chen WR, Zhou F, Yang J, Zhang Y, Liu M, Lang ML, Li M Tags: Clin Cancer Res Source Type: research

Interim PET analysis in first line therapy of multiple myeloma: Prognostic value of ΔSUVmax in the FDG-avid patients of the IMAJEM study.
CONCLUSIONS: ΔSUVmax appears to be a powerful tool for the prediction of long-term outcome in patients with FDG-avid MM. Other prospective studies are needed to further validate this prognostic biomarker. PMID: 30068709 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - August 1, 2018 Category: Cancer & Oncology Authors: Bailly C, Carlier T, Jamet B, Eugene T, Touzeau C, Attal M, Hulin C, Facon T, Leleu X, Perrot A, Garderet L, Macro M, Caillot D, Moreau P, Kraeber-Bodere F, Bodet-Milin C Tags: Clin Cancer Res Source Type: research

Regulatory T cells in ovarian cancer are characterized by a highly activated phenotype distinct from that in melanoma.
CONCLUSIONS: The highly activated phenotype of ovarian tumor-infiltrating Treg cells may be a key component of an immunosuppressive tumor microenvironment. Receptors that are expressed by tumor-infiltrating Treg cells could be exploited for the design of novel combination tumor immunotherapies. PMID: 30065096 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 31, 2018 Category: Cancer & Oncology Authors: Toker A, Nguyen LT, Stone SC, Yang C, Katz SR, Shaw PA, Clarke BA, Ghazarian DA, Al Habeeb AS, Easson AM, Leong W, McCready D, Reedijk M, Guidos CJ, Pugh TJ, Bernardini MQ, Ohashi PS Tags: Clin Cancer Res Source Type: research

Copper Chelation as Targeted Therapy in a Mouse Model of Oncogenic BRAF-Driven Papillary Thyroid Cancer.
Conclusions: TM inhibits BRAFV600E -driven PTC through inhibition of MEK1/2, supporting clinical evaluation of chronic TM therapy for this disease. Clin Cancer Res; 1-11. ©2018 AACR. PMID: 30065097 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 31, 2018 Category: Cancer & Oncology Authors: Xu M, Casio M, Range DE, Sosa JA, Counter CM Tags: Clin Cancer Res Source Type: research

Sunitinib prior to planned nephrectomy in metastatic renal cell carcinoma: angiogenesis biomarkers predict clinical outcome in the prospective Phase 2 PREINSUT trial.
CONCLUSIONS: Angiogenesis-related parameters that could reflect hypoxia seem to be associated with worse outcome in mRCC. As blood biomarkers are not subjected to tumor heterogeneity and allow longitudinal follow-up, circulating angiogenesis profile has a promising place in anti-angiogenic therapy guidance. PMID: 30061359 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 30, 2018 Category: Cancer & Oncology Authors: Mauge L, Méjean A, Fournier L, Pereira H, Etienne-Grimaldi MC, Levionnois E, Caty A, Abadie-Lacourtoisie S, Culine S, Le Moulec S, Linassier C, Théodore C, Ravaud A, Albiges L, Grine A, Tatour E, Milano G, Gille AS, Verkarre V, Helley D, Oudard SM Tags: Clin Cancer Res Source Type: research

Circulating cell-free miR-375 as surrogate marker of tumor burden in Merkel cell carcinoma.
Abstract PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. There is an unmet need for MCC-specific blood-based surrogate biomarkers of tumor burden; circulating cell-free micro(mi)RNA may serve this purpose. EXPERIMENTAL DESIGN: Expression of miR-375 was quantified in 24 MCC and 23 non-MCC cell lines, 67 MCC and 58 non-MCC tumor tissues, sera of two preclinical MCC models, sera of 109 MCC patients and 30 healthy controls by nCounter®human-v2-miRNA expression or miR-375 specific real-time PCR assays. The patients' sera consisted of two retrospective (dis...
Source: Clinical Cancer Research - July 30, 2018 Category: Cancer & Oncology Authors: Fan K, Ritter C, Nghiem P, Blom A, Verhaegen ME, Dlugosz A, Odum N, Woetmann A, Tothill RW, Hicks RJ, Sand M, Schrama D, Schadendorf D, Ugurel S, Becker JC Tags: Clin Cancer Res Source Type: research

Pathological response and survival in triple-negative breast cancer following neoadjuvant carboplatin plus docetaxel.
CONCLUSIONS: Neoadjuvant CbD yields encouraging efficacy in TNBC. Patients achieving pCR or RCB I with this regimen demonstrate excellent 3-year RFS and OS without adjuvant anthracycline. PMID: 30061361 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 30, 2018 Category: Cancer & Oncology Authors: Sharma P, López-Tarruella S, Garcia-Saenz JA, Khan QJ, Gomez H, Prat A, Moreno F, Jerez-Gilarranz Y, Barnadas A, Picornell AC, Del Monte-Millán M, Gonzalez-Rivera M, Massarrah T, Pelaez-Lorenzo B, Palomero MI, González Del Val R, Cortes J, Fuentes Rive Tags: Clin Cancer Res Source Type: research

Molecular targeted therapies elicit concurrent apoptotic and GSDME-dependent pyroptotic tumor cell death.
CONCLUSIONS: These results pinpoint GSDME-dependent pyroptosis as a previously unrecognized mechanism of action for molecular targeted agents to eradicate oncogene-addicted neoplastic cells, which may have important implications for the clinical development and optimal application of anti-cancer therapeutics. PMID: 30061362 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 30, 2018 Category: Cancer & Oncology Authors: Lu H, Zhang S, Wu J, Chen M, Cai MC, Fu Y, Li W, Wang J, Zhao X, Yu Z, Ma P, Zhuang G Tags: Clin Cancer Res Source Type: research

MELK inhibition in Diffuse Intrinsic Pontine Glioma.
CONCLUSION: We show a strong preclinical effect of the kinase inhibitor OTSSP167 in the treatment of DIPG and identify the MELK-PPARγ signaling axis as a putative therapeutic target in this disease. PMID: 30061363 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 30, 2018 Category: Cancer & Oncology Authors: Meel MH, de Gooijer MC, Guillén Navarro M, Waranecki P, Breur M, Buil L, Wedekind LE, Twisk JWR, Koster J, Hashizume R, Raabe EH, Montero Carcaboso A, Bugiani M, van Tellingen O, van Vuurden DG, Kaspers GJL, Hulleman E Tags: Clin Cancer Res Source Type: research

NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma.
CONCLUSIONS: These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immune-competent pets with cancers. PMID: 30061364 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 30, 2018 Category: Cancer & Oncology Authors: Burton JH, Mazcko CN, LeBlanc AK, Covey JM, Ji JJ, Kinders RJ, Parchment RE, Khanna C, Paoloni M, Lana SE, Weishaar K, London CA, Kisseberth WC, Krick E, Vail DM, Childress MO, Bryan JN, Barber LG, Ehrhart EJ, Kent MS, Fan TM, Kow KY, Northup N, Wilson-Ro Tags: Clin Cancer Res Source Type: research

Therapeutic targeting of TFE3/IRS-1/PI3K/mTOR axis in translocation renal cell carcinoma.
Abstract PURPOSE: Translocation renal cell carcinoma (tRCC) represents a rare subtype of kidney cancer associated with various TFE3, TFEB, or MITF gene fusions that is not responsive to standard treatments for RCC. Therefore, the identification of new therapeutic targets represents an unmet need for this disease. EXPERIMENTAL DESIGN: We have established and characterized a tRCC patient-derived xenograft (PDX), RP-R07, as a novel preclinical model for drug development by using next generation sequencing and bioinformatics analysis. We then assessed the therapeutic potential of inhibiting the identified pathway...
Source: Clinical Cancer Research - July 30, 2018 Category: Cancer & Oncology Authors: Damayanti NP, Budka JA, Khella HWZ, Ferris MW, Ku SY, Kauffman EC, Wood AC, Ahmed K, Chintala VN, Adelaiye-Ogala R, Elbanna M, Orillion AR, Chintala S, Kao C, Linehan WM, Yousef GM, Hollenhorst P, Pili R Tags: Clin Cancer Res Source Type: research

A co-clinical radiogenomic validation study - Conserved magnetic resonance radiomic appearance of Periostin expressing Glioblastoma in patients and xenograft models.
CONCLUSION: We determined causality between radiomic texture features and POSTN expression levels in a pre-clinical model with clinical validation. Our biologically validated radiomic pipeline also showed the potential application for human-mouse matched co-clinical trials. PMID: 30054278 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 27, 2018 Category: Cancer & Oncology Authors: Zinn PO, Singh SK, Kotrotsou A, Hassan I, Thomas G, Luedi MM, Elakkad A, Elshafeey N, Idris T, Mosley J, Gumin J, Fuller GN, deGroot JF, Baladandayuthapani V, Sulman EP, Kumar AJ, Sawaya R, Lang FF, Piwnica-Worms D, Colen RR Tags: Clin Cancer Res Source Type: research

Prognostic impact of residual HPV ctDNA detection after chemoradiotherapy for anal squamous cell carcinoma.
, Cacheux W Abstract PURPOSE: Chemoradiotherapy (CRT) is the current standard of care for patients diagnosed with locally advanced anal squamous cell carcinoma (ASCC), but some patients develop local and/or distant relapse during follow-up. The present study was designed to monitor HPV circulating tumor DNA (ctDNA) levels during CRT in patients with ASCC. EXPERIMENTAL DESIGN: We analyzed samples from patients with HPV16- or HPV18-positive locally advanced ASCC. Blood samples were collected before and after CRT. HPV16 or HPV18 ctDNA detection was performed by droplet digital-PCR. RESULTS: HPV ctDNA was de...
Source: Clinical Cancer Research - July 27, 2018 Category: Cancer & Oncology Authors: Cabel L, Jeannot E, Bièche I, Vacher S, Callens C, Bazire L, Morel A, Bernard-Tessier A, Chemlali W, Schnitzler A, Lièvre A, Otz J, Minsat M, Vincent-Salomon A, Pierga JY, Buecher B, Mariani P, Proudhon C, Bidard FC, Cacheux W Tags: Clin Cancer Res Source Type: research

A biologic signature for breast ductal carcinoma in situ to predict radiation therapy (RT) benefit and assess recurrence risk.
CONCLUSIONS: The DS was prognostic for risk and predicted RT benefit for DCIS patients. DS identified a clinically meaningful low risk group, and a group with elevated 10-year risks that received substantial RT benefit over baseline. PMID: 30054280 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 27, 2018 Category: Cancer & Oncology Authors: Bremer T, Whitworth P, Patel R, Savala J, Barry T, Lyle S, Leesman G, Linke SP, Jirstrom K, Zhou W, Amini RM, Wärnberg F Tags: Clin Cancer Res Source Type: research

Anti-CTLA-4 immunotherapy does not deplete FOXP3+ regulatory T cells (Tregs) in human cancers.
CONCLUSIONS: Anti-CTLA-4 immunotherapy does not deplete FOXP3+ cells in human tumors, which suggests that their efficacy could be enhanced by modifying the Fc portions of the monoclonal antibodies to enhance Fc-mediated depletion of intratumoral regulatory T cells. PMID: 30054281 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 27, 2018 Category: Cancer & Oncology Authors: Sharma A, Subudhi SK, Blando J, Scutti J, Vence L, Wargo JA, Allison JP, Ribas A, Sharma P Tags: Clin Cancer Res Source Type: research

[18F]Fluorocholine and [18F]fluoroacetate PET as imaging biomarkers to assess phosphatidylcholine and mitochondrial metabolism in preclinical models of TSC and LAM.
CONCLUSIONS: In summary, our findings provide mechanistic evidence for testing the potential of [18F]FCH and [18F]FACE as metabolic imaging biomarkers for TSC and LAM proliferative lesions, and novel insights into the metabolic reprogramming of TSC tumors. PMID: 30054282 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 27, 2018 Category: Cancer & Oncology Authors: Verwer EE, Kavanagh TR, Mischler WJ, Feng Y, Takahashi K, Wang S, Shoup TM, Neelamegam R, Yang J, Guehl NJ, Ran C, Massefski W, Cui Y, El-Chemaly S, Sadow PM, Oldham WM, Kijewski MF, El Fakhri G, Normandin MD, Priolo C Tags: Clin Cancer Res Source Type: research

Brain development and heart function after systemic single-agent chemotherapy in a mouse model of childhood leukemia treatment.
CONCLUSION: Multiple ALL chemotherapy agents can affect postnatal brain development or heart function. This study provides a ranking of agents based on potential toxicity, and thus highlights a subset likely to cause side effects in early adulthood for further study. PMID: 30054283 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 27, 2018 Category: Cancer & Oncology Authors: Spencer Noakes TL, Przybycien TS, Forwell A, Nicholls CJ, Zhou YQ, Butcher DT, Weksberg R, Guger SL, Spiegler BJ, Schachar RJ, Hitzler J, Ito S, van der Plas E, Nieman BJ Tags: Clin Cancer Res Source Type: research

Prognostic significance of tumor-infiltrating B cells and plasma cells in human cancer.
Abstract There is abundant evidence that tumor-infiltrating CD8+ T cells contribute positively to anti-tumor immunity; however, the role of tumor-infiltrating B cells (TIL-B) and plasma cells (PC) remains controversial, leading to differing opinions about whether immunotherapies should be designed to enhance or inhibit these cells. Through a comprehensive PubMed search, we reviewed publications with cohorts of 50 or more cases in which the prognostic value of TIL-B/PC was assessed by immunohistochemistry and/or gene expression analysis. Sixty-nine studies representing 19 cancers met our review criteria. The large ...
Source: Clinical Cancer Research - July 26, 2018 Category: Cancer & Oncology Authors: Wouters MC, Nelson BH Tags: Clin Cancer Res Source Type: research

Blocking monocytic myeloid-derived suppressor cell function via anti-DC-HIL/GPNMB antibody restores the in vitro integrity of T-cells from cancer patients.
CONCLUSIONS: Blocking DC-HIL function is a potentially useful treatment for at least colorectal cancer with high blood levels of DC-HIL+ MDSCs. PMID: 30049749 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 26, 2018 Category: Cancer & Oncology Authors: Kobayashi M, Chung JS, Beg M, Arriaga Y, Verma UN, Courtney K, Mansour JC, Haley B, Khan SA, Horiuchi Y, Ramani V, Harker D, Gopal P, Araghizadeh F, Cruz PD, Ariizumi K Tags: Clin Cancer Res Source Type: research

Real-time Tumor Gene Expression Profiling to Direct Gastric Cancer Chemotherapy: Proof-of-Concept '3G' Trial.
Conclusions This bench-to-bedside effort establishes a reasonable turnaround time for gene expression profiling and possible utility of genomic classifiers in gastric cancer treatment stratification. PMID: 30045931 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 25, 2018 Category: Cancer & Oncology Authors: Yong WP, Rha SY, Tan IB, Choo SP, Syn NL, Koh V, Tan SH, Asuncion BR, Sundar R, So JBY, Shabbir A, Tan CS, Kim HS, Jung M, Chung HC, Ng MC, Tai D, Lee M, Wu J, Yeoh KG, Tan P Tags: Clin Cancer Res Source Type: research

Phase I Trial of ALT-803, a Novel Recombinant Interleukin-15 Complex, in Patients with Advanced Solid Tumors.
CONCLUSIONS: Subcutaneous ALT-803 produced the expected NK cell expansion and was well-tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in advanced cancer patients. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anti-cancer agents. PMID: 30045932 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 25, 2018 Category: Cancer & Oncology Authors: Margolin K, Morishima C, Velcheti V, Miller JS, Lee SM, Silk AW, Holtan SG, Lacroix AM, Fling SP, Kaiser JC, Egan JO, Jones M, Rhode PR, Rock AD, Cheever MA, Wong HC, Ernstoff MS Tags: Clin Cancer Res Source Type: research

Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers.
Abstract PURPOSE: Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored. EXPERIMENTAL DESIGN: We identified all patients with metastatic EGFR exon19del or L858R mutant lung cancers treated with first/second generation EGFR tyrosine kinase inhibitors (TKIs) with pre-treatment large panel next generation sequencing data (MSK-IMPACT assay). The effect of TMB on time to treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. EGFR wild-type (WT)...
Source: Clinical Cancer Research - July 25, 2018 Category: Cancer & Oncology Authors: Offin M, Rizvi H, Tenet M, Ni A, Sanchez-Vega F, Li BT, Drilon A, Kris MG, Rudin CM, Schultz N, Arcila ME, Ladanyi M, Riely GJ, Yu H, Hellmann MD Tags: Clin Cancer Res Source Type: research

Single-molecule sequencing reveals patterns of pre-existing drug resistance that suggest treatment strategies in Philadelphia-positive leukemias.
CONCLUSION: These results argue that early use of therapies that achieve pan-inhibition of ABL1 resistance mutants might improve outcomes in Ph+ ALL. Our findings show how a deep understanding of the mutational burden in drug targets can be quantitatively coupled to phenotypic heterogeneity to rationalize clinical phenomena. PMID: 30042204 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 24, 2018 Category: Cancer & Oncology Authors: Schmitt MW, Pritchard JR, Leighow SM, Aminov BI, Beppu L, Kim DS, Hodgson JG, Rivera VM, Loeb LA, Radich J Tags: Clin Cancer Res Source Type: research

Resistance to radiotherapy and PD-L1 blockade is mediated by TIM-3 upregulation and regulatory T-cell infiltration.
CONCLUSIONS: These data reveal multiple layers of immunoregulation that can promote tumorigenesis, and the therapeutic potential of sequential targeting to overcome tumor resistance mechanisms. We propose that targeted Treg inhibitors may be critical for achieving durable tumor response with combined radiotherapy and immunotherapy. PMID: 30042205 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 24, 2018 Category: Cancer & Oncology Authors: Oweida A, Hararah M, Phan AV, Binder DC, Bhatia S, Lennon S, Bukkapatnam S, Van Court B, Uyanga N, Darragh L, Kim HM, Raben D, Tan AC, Heasley L, Clambey ET, Nemenoff RA, Karam SD Tags: Clin Cancer Res Source Type: research

Class matters: Sensitivity of BRAF-mutant melanoma to MAPK inhibition.
Abstract Mutations in BRAF outside of the 600 codon (BRAF non-V600) occur across cancer types, including in 3-5% of melanomas. The optimal treatment strategies are not clear, but could include MEK inhibitors based on pre-clinical studies. Combining BRAF and MEK inhibitors in this population may provide additional benefit. PMID: 30042206 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 24, 2018 Category: Cancer & Oncology Authors: Johnson DB, Dahlman KB Tags: Clin Cancer Res Source Type: research

The proteome of prostate cancer bone metastasis reveals heterogeneity with prognostic implications.
CONCLUSIONS: This work is the first system-wide quantitative characterization of the proteome of PCa bone metastases and a valuable resource for understanding the etiology of PCa progression. PMID: 30042207 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 24, 2018 Category: Cancer & Oncology Authors: Iglesias-Gato D, Thysell E, Tyanova S, Crnalic S, Santos A, Lima TS, Geiger T, Cox J, Widmark A, Bergh A, Mann M, Flores-Morales A, Wikström P Tags: Clin Cancer Res Source Type: research

Immunomarker Support Vector Machine Classifier for Prediction of Gastric Cancer Survival and Adjuvant Chemotherapeutic Benefit.
CONCLUSION: The newly developed GC-SVM classifier was a powerful predictor of OS and DFS. Moreover, the GC-SVM classifier could predict which patients with stage II and III GC benefit from adjuvant chemotherapy. PMID: 30042208 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)
Source: Clinical Cancer Research - July 24, 2018 Category: Cancer & Oncology Authors: Jiang Y, Xie J, Han Z, Liu W, Xi S, Huang L, Huang W, Lin T, Zhao LY, Hu YF, Yu J, Zhang Q, Li T, Cai SR, Li G Tags: Clin Cancer Res Source Type: research