tbuckley/cabot-search huggingface dataset:
Abstract A070: Targeting N-myristoyltransferase 1 inhibits prostate cancer progression
Authors: Omar Alsaidan, Sungjin Kim, Octavia Goodwin, Qianjin Li, Aiping Bai, Alicja Bielawska, George Zheng, Iryna Lebedyeva, Thomas Albers, James S. Norris, Scott D. Pegan, Houjian Cai
Journal: Cancer Research (2018)

Abstract N-myristoyltransferase (NMT) facilitates co/post-translational myristoylation of several oncogenic proteins, regulating their functions in tumor progression. N-myristoyltransferase (NMT), which has been shown to be upregulated in a variety of cancers, is overexpressed in androgen-independent prostate cancer cells. We demonstrate that genetically, ablation of NMT1 inhibited proliferation of prostate cancer cells, tumor growth, and suppressed myristoylation profile of prostate cancer cells. Screening a panel of myristoyl-CoA analogs against purified human NMT1 protein leads to identifying the B13 as an inhibitor for NMT1. B13 significantly suppressed prostate cancer cell proliferation, migration, and invasion by cell cycle arrest, and inhibited the growth of prostate xenograft tumors with minimal pathologic effect on major organs in vivo. Structure activity relationship based optimization of B13 led to LCL204, which showed better inhibitory properties towards NMT1. We demonstrate that targeting protein myristoylation is a potential therapeutic approach to inhibit prostate tumor progression. Citation Format: Omar Alsaidan, Sungjin Kim, Octavia Goodwin, Qianjin Li, Aiping Bai, Alicja Bielawska, George Zheng, Iryna Lebedyeva, Thomas Albers, James S. Norris, Scott D. Pegan, Houjian Cai. Targeting N-myristoyltransferase 1 inhibits prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A070.
Serum metabolism during breast cancer treatment.
Authors: Guro Fanneløb Giskeødegård, Torfinn Støve Madssen, Riyas Vettukattil, Vidar Gordon Flote, Anders Husøy, Trygve Lofterød, Steinar Lundgren, Gro Falkener Bertheussen, Ellen Schlichting, Erik Andreas Wist, Inger Thune, Tone Frost Bathen
Journal: Journal of Clinical Oncology (2017)

e23043 Serum metabolism during breast cancer treatment Background: Breast cancer treatment may include surgery, systemic therapy and radiation, often involving side-effects. Many patients experience weight gain during treatment, which is associated with decreased survival rates 1 . The purpose of this study was to describe serum metabolic alterations in breast cancer patients undergoing treatment, and relate these alterations to weight gain during treatment. Methods: This pilot study includes 60 breast cancer patients, aged 35-75 years, with histologically verified stage I/II disease. All patients underwent tumor surgery, and were treated according to national guidelines. Samples were collected before and 6 months after surgery, and analyzed by MR spectroscopy (MRS) and mass spectrometry (MS). 170 metabolites and 105 lipoprotein subfractions were quantified by combined MRS and MS analyses. Results: Multilevel PLS-DA showed significant alterations in serum metabolite profiles post-treatment, both in patients receiving (n = 35) and not receiving (n = 25) chemotherapy (classification accuracy: 86.7% and 77.0%, resp., p &lt; 0.001). Lipoprotein profiles were also significantly altered in both groups (p &lt; 0.001). Chemotherapy recipients had decreased levels of citrate, ornithine, and methionine after treatment, while non-recipients had increased levels of glutamate, alanine, proline and two biogenic amines, and decreased levels of acylcarnitines. 17/52 patients (32.7%) gained weight (≥ 1.5 kg) during treatment. Weight gain was predicted from pre-treatment samples with accuracy 67.0% (p = 0.020). Weight gain patients had lower levels of three acylcarnitines and 20 phosphocholines, and higher levels of lysine and isoleucine, suggesting aberrant lipid and amino acid metabolism. Weight gain was also reflected in the post-treatment samples (accuracy 66.8%, p = 0.015), with weight gain patients having higher levels of five acylcarnitines, and lower levels of glycine, isoleucine and valine. Conclusions: This study indicates that treatment induces changes in serum metabolite levels. Patients gaining weight had significantly different metabolite profiles than those not gaining weight both before and after treatment. 1. Chan et al, Ann Oncol 25: 1901-14, 2014.
Targeted next generation sequencing (NGS) of matched primary tumor, metastasis, circulating tumor cells (CTCs), and cell-free DNA (cfDNA) in a patient with advanced prostate cancer (PC).
Authors: Cory Michael Hugen, Pamela Ward, Jonas Petterson, Louis Dubeau, Paul W. Dempsey, Brian Robin Hu, Tong Xu, David I. Quinn, Amir Goldkorn
Journal: Journal of Clinical Oncology (2016)

e23057 Background: NGS of primary prostate tumors and metastases has illuminated patterns of clonal dissemination, but tissue from multiple sites often is not available in clinical settings. Liquid biopsies are minimally invasive and readily obtained via serial blood draws. We compared genomic alterations detected in primary tissue and metastatic sites with liquid biopsy results from circulating tumor cells (CTCs) and cfDNA. Methods: 7.5ml blood samples from men with metastatic castration resistant PC (mCRPC) were processed using LiquidBiopsy (Cynvenio), an immunomagnetic enrichment platform (EpCAM+CK+DAPI+CD45- ) that yielded a CTC-enriched pellet and matched plasma from each sample. DNA was extracted for targeted NGS (AmpliSeq 2.0, Life Technology) on an Ion Torrent System. Somatic single nucleotide variants (SSNVs) occurring in > 1% of DNA were identified based on presence in CTCs or plasma and absence in a matched WBC pellet and validated by ddPCR (RainDance). Archived FFPE primary and metastatic tumors were analyzed similarly. Results: To date, matched samples have been collected from 5 patients. In one patient with complete data from all tissues, targeted NGS yielded concordant SSNVs in TP53 (p.R175H) and PTEN (p.R130*) in a 2008 prostatectomy tissue (5% and 4% allele frequencies; respectively), a 2014 supraclavicular lymph node biopsy (43% and 36%), and 2014 plasma cfDNA (5% and 4%, confirmed by ddPCR: 7% and 3%). A follow-up plasma cfDNA sample 3 months later had 13% and 5% by ddPCR. NGS of CTC DNA from the same 2014 blood sample identified SSNVs at different loci within the same genes (TP53 c.165-1G > C at 1%; PTEN p.D186N at 1%). Conclusions: Concordant DNA alterations reflecting clonal dissemination were identified by targeted NGS of primary PC and at higher frequency in a metastasis 6 years later. Concurrent liquid biopsy samples detected concordant SSNVs in cfDNA (confirmed by ddPCR), whereas CTC DNA yielded different SSNVs. Expanded prospective cohorts are ongoing to further elucidate which tissue sources, alone or in combination, yield genomic data that best predict clinical outcomes.
Glucocorticoid (GC) Induced Cytokine Expression in CD4+ T Cells Is a Candidate Biomarker for Clinical Steroid Response in Patients with Immune Thrombocytopenia
Authors: Charlotte A Bradbury, Madeleine L. Stimpson, Philippa J.P. Lait, Lauren P. Schewitz-Bowers, Emily L. Williams, Kimberley Thirlwall, Benjamin Chaigne-Delalande, Richard W.J. Lee
Journal: Blood (2017)
Clinically Localized Prostate Cancer: ASCO Clinical Practice Guideline Endorsement of an American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology Guideline
Authors: Justin E. Bekelman, R. Bryan Rumble, Ronald C. Chen, Thomas M. Pisansky, Antonio Finelli, Andrew Feifer, Paul L. Nguyen, D. Andrew Loblaw, Scott T. Tagawa, Silke Gillessen, Todd M. Morgan, Glenn Liu, Neha Vapiwala, John J. Haluschak, Andrew Stephenson, Karim Touijer, Terry Kungel, Stephen J. Freedland
Journal: Journal of Clinical Oncology (2018)

In April 2017, the American Urological Association, American Society for Radiation Oncology, and Society of Urologic Oncology released a joint evidence-based practice guideline on clinically localized prostate cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations.The Clinically Localized Prostate Cancer guideline was reviewed for developmental rigor by methodologists. An ASCO Expert Panel then reviewed the content and the recommendations.The ASCO Expert Panel determined that the recommendations from the Clinically Localized Prostate Cancer guideline were clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the Clinically Localized Prostate Cancer guideline except for two recommendations on cryosurgery. The two recommendations covering cryosurgery were not endorsed because the panel found that there is insufficient evidence to support the use of cryotherapy in this setting.The ASCO Expert Panel endorsed all but two of the original guideline recommendations as written and offered a series of discussion points to guide practice.
LUX-head and neck 2: Randomized, double-blind, placebo-controlled, phase III trial of afatinib as adjuvant therapy after chemoradiation (CRT) in primary unresected, high/intermediate-risk, squamous cell cancer of the head and neck (HNSCC) patients (pts).
Authors: Barbara Burtness, Robert I. Haddad, José Dinis, Jose Manuel Trigo Perez, Tomoya Yokota, Luciano De Souza Viana, Ilya Romanov, Jan Baptist Vermorken, Jean Bourhis, Makoto Tahara, J.G.M. Segalla, Amanda Psyrri, Irina Vasilevskaya, Chaitali Singh Nangia, Manuel Chaves-Conde, Bushi Wang, Neil Gibson, Eva Ehrnrooth, Kevin Harrington, Ezra E.W. Cohen
Journal: Journal of Clinical Oncology (2017)

6001 Background: Locally advanced HNSCC is treated curatively, but recurrence is common. In HNSCC, EGFR is richly expressed and EGFR inhibition is validated treatment (tx); the ErbB family blocker afatinib (A) showed efficacy in recurrent/metastatic disease. This Phase III trial assessed if A after definitive CRT improves disease-free survival (DFS). Methods: Eligible pts had complete response after CRT ≥66 Gy (or equivalent) with concurrent cisplatin or carboplatin but not prior EGFR inhibition, for HNSCC of oral cavity, hypopharynx, larynx, or oropharynx with &gt;10 pack years (pk yrs) tobacco use. Pts were stratified by ECOG PS (0/1) and nodal stage (N0–2a/N2b–3), and randomized 2:1 to A 40 mg/d or placebo (P); tx continued for 18 m if tolerated, or until disease recurrence. The primary endpoint was DFS. Results: Of 669 pts planned, 617 were randomized; A 411, P 206. Median age was 58 yrs; 86% were male; 65% ECOG PS 0; most had smoked (A/P ex-smoker: 66/72%; current: 28/22%). Subsites (A/P) were: oropharynx 53/54%; hypopharynx 21/23%; larynx 18/12%; oral cavity 9/10%. The majority had T3 or 4 (A/P 70/68%) and N2 disease (67/63%). Accrual was halted for futility on independent DMC recommendation: at a pre-planned interim analysis (40% of DFS events), median DFS was A 43.4 m vs P not reached (NR; HR 1.13 [95% CI 0.81–1.57], p=0.48); the Table shows key subgroups. Median treatment duration was A 300.0 d, P 455.5 d. Recurrence was A 23%, P 23%. Dose reduction of A was required in 53% (mostly due to diarrhea, stomatitis). Tx was discontinued due to AEs in A 15%, P 4%. Conclusions: A after CRT did not improve DFS vs P. Subgroup analyses were underpowered to provide definitive conclusions. Harrington and Cohen contributed equally. Clinical trial information: NCT01345669. [Table: see text]
Association of abnormal molecular markers with clonal plasma cell burden in light chain amyloidosis.
Authors: Lindsay Hammons, Parameswaran Hari, Ruta Brazauskas, Anita D'Souza
Journal: Journal of Clinical Oncology (2016)

8063 Background: Light chain amyloidosis (AL) is a clonal plasma cell neoplasm in which clonal light chains misfold into amyloid and deposit in tissues. The pathogenesis of AL depends on the degree of systemic deposition of amyloid fibrils into vital organs. AL shares a plethora of chromosomal abnormalities with multiple myeloma (MM) given the underlying common plasma cell neoplasm. Also, overall survival of AL is affected by the size of the underlying plasma cell clones due to the capacity of fibril-producing plasma cells to ‘recruit’ other less-stable light chains to make protein aggregates. The purpose of our study was to assess specific genetic abnormalities found on conventional karyotype and CD138-enriched FISH studies and to correlate findings between MM molecular markers found in AL with organ involvement, stage and prognosis. Methods: Retrospective study reviewed 107 patients with systemic AL using multiple myeloma-guided FISH and cytogenetic studies from our institution from Jan 2010 until Jan 2015. The study also looked at demographic factors, clinical presentations, organ involvement, light chain clone, clonal plasma cells, cardiac biomarkers (cTnT, NT-proBNP), and clinical outcomes of patients. Results: Forty-one percent of patients had abnormal FISH. Common abnormalities included t(11;14) (14%), t(4;14) (1%), del17p (4%) and 1q (4%). Other abnormalities included polysomy 11 (13%) and monosomy 13 (9%). Twenty-one percent of our population had hyperdiploidy and about 11% had hypodiploidy. Abnormal FISH studies significantly increased the probability of having plasma cell involvement ≥ 10% (p = 0.002). FISH abnormalities were not shown to correlate with race, cardiac 2004 staging, cardiac involvement or early mortality. Conclusions: The presence of abnormal molecular markers was associated with clonal plasma cell burden in AL. The biological behavior and clinical outcome in AL, much like those in MM, appear to be dependent on molecular determinants that could serve as attractive future therapeutic targets and predictive prognostic variables. Further work is needed in larger cohorts of AL patients to assess if cytogenetic markers affects prognosis and/or outcomes of AL amyloidosis.
P04.83 Additive effect of tonabersat on standard medical treatment in glioblastoma: preliminary results
Authors: V de Meulenaere, E Bonte, J Verhoeven, J Kalala Okito, L Leybaert, C Vanhove, B Descamps, K Deblaere
Journal: Neuro-Oncology (2018)

Glioblastoma (GB) is the most common primary malignant brain tumor in adults. Currently, standard medical treatment consists of maximal surgical resection followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). The median survival from diagnosis is ± 15 months. Hence, there is an urgent need for effective therapies that act on GB and improve survival outcomes. GB cells can connect via tumor microtubes based on connexin 43 gap-junctions. These tumor microtubes allow communication between tumor cells and play an important role in potential resistance against radiotherapeutic damage. In this preclinical study, we evaluated the possible additive effect of tonabersat as a connexin modulator on standard medical treatment in the F98 GB rat model. Female Fischer rats were inoculated with ± 25.000 F98 tumor cells in the right frontal lobe. 7 days post-inoculation T1w MR images were acquired to confirm tumor growth in the rat brain. When the tumor volume was approximately 20 mm3, the rats were randomized into a sham group (n=10) receiving control injections, a standard medical treatment group (n=4) receiving RT with concomitant TMZ (IP injections for 5 days; 29 mg/kg) and a connexin modulator group (n=6) receiving RT with concomitant TMZ and additive treatment with tonabersat (daily IP injections, 10 mg/kg). RT was performed using MRI-guided conformal arc treatment (20 Gy, 3 non-coplanar arc beams, 5x5 mm collimator) with the Small Animal Radiation Research Platform. To evaluate therapy response, contrast-enhanced T1w MRI sequences were run at day 3, 6, 10, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35 and 37 (day 1 = start of standard medical treatment or first control injection). Tumor growth was statistically evaluated using Kruskal-Wallis and Mann-Whitney U test. The tumors in the control group showed rapid proliferation during follow-up, encompassing almost the entire right cerebral hemisphere at day 12–15 leading to early euthanasia. On day 10 and 13, a significant difference in tumor growth was observed between the control group and the standard medical treatment group (p=0,001 and p=0,003, respectively) and between the control group and the connexin modulator group (p=0,001 and p=0,003, respectively). On day 15, the significant difference was only observed between the control group and the connexin modulator group and no longer between the control group and standard medical treatment group. A significant difference in tumor growth on day 19 and 21 was observed between the standard medical treatment group and the connexin modulator group (p=0,016 and p=0,036, respectively). Evaluation of tumor growth showed a trend towards longer stagnation of the tumor volume in the connexin modulator group compared to the standard medical treatment group, which may indicate the possible additive effect of tonabersat.
First report of safety, PK, and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788 (AP32788) in non–small cell lung cancer (NSCLC).
Authors: Robert Charles Doebele, Gregory J. Riely, Alexander I. Spira, Leora Horn, Zofia Piotrowska, Daniel Botelho Costa, Joel W. Neal, Steven Zhang, William Reichmann, David Kerstein, Shuanglian Li, Pasi A. Janne
Journal: Journal of Clinical Oncology (2018)

9015 Background: TAK-788 is an investigational TKI with potent, selective preclinical activity against activating EGFR and HER2 mutations, including exon 20 insertions. We report the first results of a phase 1/2 first-in-human, open-label, multicenter study of TAK-788 (NCT02716116). Methods: Pts with advanced NSCLC refractory to standard therapy received daily oral doses (5–120 mg) of TAK-788 in the ongoing dose-escalation phase (3+3 design). Preliminary antitumor activity (by RECIST v1.1), safety, and PK are reported for pts receiving ≥1 dose. Results: As of 8 September 2017, 34 pts (median age, 60 y; female, 65%; ≥2 prior anticancer therapies, 88%; Table) were treated and 10 remain on TAK-788 at data cutoff. AUC0-24,ss increased in a dose-proportional manner over the dose range with effective t1/2 of ∼16 (range 6–28) h. Most common treatment-emergent AEs (TEAEs; ≥20% of pts): diarrhea (47%), nausea (26%), fatigue (21%). Grade ≥3 TEAEs in ≥2 pts (excluding disease progression): dyspnea (n = 3, 9%); anemia, asthenia, dehydration, lung infection, pleural effusion, pneumonia, pneumonitis (n = 2 each, 6%). Two DLTs, both pneumonitis, were reported (80 mg, grade 3; 120 mg, grade 5). Of 14 evaluable pts, 3 had PR (80 mg, n = 2, both confirmed; 120 mg, single PR awaiting confirmation), 6 had SD (40 mg, n = 3; 80 mg, n = 2; 120 mg, n = 1), and 5 had PD as best response (40 mg, n = 3; 80 mg, n = 1; 120 mg, n = 1); all pts with PR or SD had EGFR exon 20 insertions. Conclusions: TAK-788 exhibits antitumor activity in pts with EGFR exon 20 insertions with an AE profile consistent with other EGFR TKIs. Phase 2 will begin after determination of the RP2D, with 4 molecularly defined cohorts in NSCLC.Clinical trial information: NCT02716116.Baseline characteristics. 5 mg (n = 4) 10 mg (n = 5) 20 mg (n = 5) 40 mg (n = 6) 80 mg (n = 7) 120 mg (n = 7) Total (n = 34) Mutation type,a % Common EGFR mutations (exon 19 deletion / L8585R) 25 20 0 0 0 0 6 EGFR-T790M+ 0 0 0 0 14 0 3 EGFR exon 20 insertion 50 40 60 83 71 57 62 HER2 0 20 40 17 14 29 21 aOne pt (20 mg) had both EGFR and HER2 mutations; 1 pt (80 mg) had EGFR exon 20 insertion + T790M.
First-line therapy with fulvestrant (FUL) in HR+ve, HER2-ve advanced pre-treated breast cancer (ABC) patients (pts): Results from the GIM-13 AMBRA Study.
Authors: Paolo Pronzato, Giorgio Mustacchi, Monica Giordano, Ornella Garrone, Lucia Del Mastro, Clara Natoli, Anna Turletti, Emanuela Romagnoli, Alessandra Bologna, Carmela Mocerino, Massimiliano Alù, Claudia De Angelis, Caterina Aversa, Grazia Arpino, Cristiana Taverniti, Laura Biganzoli, Icro Meattini, Michela Piezzo, Marina Elena Cazzaniga
Journal: Journal of Clinical Oncology (2018)

e13032 Background: Endocrine therapy (ET) is the initial therapy for HR+ patients. Primary endocrine resistance (PER) is defined as a relapse while on the first 2 years of adjuvant ET, or PD within first 6 months of first-line ET for MBC; secondary endocrine resistance (SER) is defined as: relapse while on adjuvant ET but after the first 2 years, or relapse within 12 months of completing adjuvant ET, or PD > 6months after initiating ET for MBC. One of the available therapeutic strategy is FUL, which demonstrated in a recent Phase III trial, PFS was significantly longer in the FUL group than in the ANA group (16.6 vs 13.8 months). Aim of the present analysis is to describe pts’ characteristics and clinical outcome in a population of endocrine-pretreated pts who received FUL as 1st-line therapy in a real-life setting. Methods: We used data of the HR+ve pts of the AMBRA study, a longitudinal cohort study, describing the choice of first and subsequent lines of treatment in HER2-ve MBC pts, treated with FUL in any line of therapy to describe pts’ characteristics and outcome in terms of ORR (CR+PR) and DCR (ORR+SD) and time to treatment change (TTC). Results: So far, 791/1500 pts have been registered into the AMBRA study, 673 of them (85%) with HR+ ABC: 139 have received FUL as 1st-line therapy. Median age was 56 years (21-82). 108 pts (77.7%) have received adjuvant Aromatase Inhibitors (AIs), alone (56, 51.9 %) or as part of a sequential therapy with Tamoxifen (TAM). Median DFI was 81.4 months (1.1-427.4), 82.1 months (6.2 – 427.4) in pts who received adjuvant chemotherapy (CHT) and 69.5 months (0.5 – 176.6) in those treated with adjuvant ET alone. Eighteen pts showed a DFI < 24 months and can be considered as PER pts. In pts treated with FUL as 1st-line therapy, median Time to Treatment Change (TTC) was 19.0 months (0.5-37.1) in PER pts and 90.2 months (26.3-427.4) in SER ones. Conclusions: Although the small sample size and the retrospective analysis, our data from the real world seem to suggest that FUL is much more active in progression delay in pts with secondary endocrine resistance than in those who had a short DFI and are considered PER pts. Further data are warranted to confirm these findings.
Colorectal cancer risk in Li-Fraumeni syndrome: Is it time for earlier surveillance?
Authors: Suzanne Macfarland, Kristin Zelley, Jessica M. Long, Danielle Mckenna, Garrett M. Brodeur, Anil K. Rustgi, Bryson W Katona, Kara Noelle Maxwell
Journal: Journal of Clinical Oncology (2018)

e13503 Background: Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome caused by mutations in TP53. LFS patients have an increased risk for colorectal cancer (CRC) and surveillance is currently recommended starting at age 25. Methods: Retrospective analysis of 91 LFS patients at a pediatric/adult tertiary referral center. Results: Retrospective analysis demonstrated an 8.8% incidence of CRC and high-grade dysplasia in LFS patients. In this cohort, 3% of patients developed CRC prior to the age of 25. Conclusions: These data suggest that CRC screening should begin at a younger age than is currently recommended.