tbuckley/cabot-search huggingface dataset:
A randomized, double-blind, placebo-controlled trial for prevention of oxalipatin-induced peripheral neuropathy symptoms with pregabalin in patients with advanced colorectal cancer.
Authors: M. Karthaus, C. S. Karapetis, M. P. Brown, N. Pavlakis, T. Trarbach, N. Marschner, H. A. Duerk, C. Barone, M. Luigi
Journal: Journal of Clinical Oncology (2010)

e19573 Background: Sensorial peripheral neuropathy (PNP) is a major limitation for pts receiving oxaliplatin based ctx for CRC. Pregabalin is widely used for treatment of oxaliplatin induced PNP. We evaluated the efficacy of pregabalin vs. placebo for the prevention of paresthesia from the onset of oxaliplatin based ctx over each cycle. Methods: Rd, db, placebo-controlled study in adult CRC pts with ECOG 0-2 to undergo a new oxaliplatin/5-FU/FA based ctx. Pts were excluded if they had neuropathic pain or other of painful paresthesia prior to baseline. Paresthesia, dysesthesia, and pain were rated on a numerical rating scale (NRS 0-10) every day. Primary endpoint was the time of onset of persistent symptoms (NRS >4). Results: Of the 69 screened pts, 64 were randomized and 61 received study medication (32 pregabalin vs 29 placebo). Pts were balanced in both arms regarding age, sex, stage and ctx. There were no differences between both treatment groups for all PNP parameters at any cycle. One pt in both arms developed paresthesiae (5.3%) after 9 cycles of ctx, 1 pt had persistent pain (placebo arm). During the follow-up period, persistent paresthesiae, dysesthesiae and persistent pain (pregabalin vs. placebo) developed in 2 vs. 1, 2 vs. 2 and 0 vs. 2 pts, respectively. The study was terminated when the interim analysis showed no difference in treatment groups. Nausea and anorexia were the most frequently reported AE in both groups. Conclusions: The results presented that too few patients developed persistent PNP symptoms to allow any meaningful treatment difference. Whether pregabalin for prevention of oxaliplatin induced PNP was not effective in CRC pts could however not be ruled out. Since there is an unmet need for oxaliplatin associated PNP further pregabalin trials with modified assessment of PNP are warranted. There was no safety concern noted for pts receiving pregabalin for prophylaxis of PNP. No significant financial relationships to disclose.
We Are Standing on the Shoulders of Giants
Authors: Anton Berns
Journal: Cancer Research (2016)

See related article by Olson, [Cancer Res 1941;1:384–92][1] .

Visit the Cancer Research 75th Anniversary [timeline][2].

Being asked to write a commentary on an article published in the first volume of Cancer Research ([1][3]), celebrating its 75th anniversary, I said somewhat reluctantly “yes
Abstract 672: Differential effects of p53 mutations on cancer invasion and metastasis in a mouse model of colon cancer
Authors: Ying Feng, Naoya Sakamoto, Maranne Green, Megan Greenn, Kathleen R. Cho, Eric R. Fearon
Journal: Cancer Research (2016)

Abstract Inactivation of the APC (adenomatous polyposis coli) tumor suppressor gene plays an important role in initiating most adenomas and colorectal cancers (CRCs). Somatic mutations in the TP53 tumor suppressor gene and KRAS oncogene are found in roughly 60% and 40% of CRCs, respectively, and contribute to tumor progression. In the vast majority of human CRCs, TP53 missense mutations lead to high levels of mutant p53 protein expression and the loss of the other wild type TP53 allele. To evaluate the role of TP53 missense mutations in CRC progression, we generated a genetically engineered mouse model of colorectal carcinoma, via combined targeting of Apc, Kras, and Trp53 alleles in mouse colon epithelium, focusing on comparing phenotypic effects of the murine equivalent of the human R273H mutation (i.e., murine R270H mutation) or a large deletion mutation of mouse Trp53. Inactivation of one allele Apc and activation of an oncogenic Kras allele in colon epithelium generated serrated and hyperplastic morphologic epithelium and adenomas. The addition of either the R270H missense mutation or the Trp53 null mutation to the Apc and Kras mutations led to markedly shortened survival of the mice, due to the development of multiple colon tumors in each mouse ranging from adenomas to late stage adenocarcinomas. Evidence of invasion into the smooth muscle and serosa area was found in both compound mice with missense or deletion mutations in Trp53, with the Trp53R270H mutant mice displaying an increased prevalence of deeply invasive tumors relative to the mice with deletion of Trp53. Furthermore, we found that the missense mutant Trp53R270H allele in combination with Apc and Kras mutations, but not the null-mutant Trp53 allele, was strongly linked to metastases to lymph nodes and lung. We have developed a useful mouse model of metastatic colon cancer that recapitulates the role of TP53 mutations in cooperating with APC and KRAS mutations in human CRC development and progression. In addition, our findings strongly suggest a powerful role for missense mutant p53 proteins compared to TP53 null mutations in promoting invasion and metastasis in CRC progression. Citation Format: Ying Feng, Naoya Sakamoto, Maranne Green, Megan Greenn, Kathleen R. Cho, Eric R. Fearon. Differential effects of p53 mutations on cancer invasion and metastasis in a mouse model of colon cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 672.
Abstract 753: The use of proteomics to analyse whole tumors and identify unique stroma cell targets for antibody-based therapeutics
Authors: James Ackroyd, Jason Allen, Jo Berry, Lisa Roesch, Martin Barnes, Arnima Bisht, Christian Rohlff, Keith Wilson, Dee Aud, Robert Boyd
Journal: Cancer Research (2016)

Abstract Solid tumors comprises of two distinct compartments: cancer cells and the stroma that the cancer cells induce and are dispersed in. This stroma contains stromal (Fibroblasts, endothelial and pericyte cells) and infiltrating immune cells (Lymphocytes, macrophages, granulocytes and myeloid derived suppressor cells). Recent oncology research has implicated these stroma cells as promoters of tumor progression and there is thus a strong need to profile the cell membrane proteins present on these cells. For tumors which do not contain infiltrating T cells (non-immunogenic tumors) it has been recognized that it will be necessary to employ therapeutic agents to disrupt the tumor micro-environment (TME); allowing the release and processing of tumor antigens by antigen presenting cells, entry and migration T cells into intrastromal sites and potent activation of T cell responses to tumor antigens. We have conducted in-depth proteomic profiling of tumors from 14 different solid cancer indications with varying degrees of stroma involvement to characterize their immune and stromal cell composition. The data from this work was analyzed in OGAP®; a unique proteomic database that integrates information at the tissue, disease and protein isoform level across diseases, indications, and normal tissues to clarify membrane protein expression levels and profiles. It is one of the world's largest proprietary cell-membrane focused proteomic database, with data on over 5000 cancer membrane proteins. Purified stroma cell populations were also profiled to facilitate the interpretation of whole tumor proteomic data. Cell membrane proteins present in tumors from different cancer indications were analyzed by mass spectrometry. We classified tumors as immunogenic or non-immunogenic using validated T cell markers (CD3, CD4, CD8 and CD69). We then profiled the non-immunogenic tumors for fibroblast, macrophage and B cell type markers to try and identify strong stroma cell expression patterns not detected in normal tissues. Importantly, most current antibody therapeutic stroma cell targets (CSF-1R, FAP and VEGF-A) were re-discovered. Several novel stroma cell therapeutic targets were identified which if targeted by a therapeutic antibody have the potential to enhance the T cell immune response in tumors resistant to current immunotherapy. Citation Format: James Ackroyd, Jason Allen, Jo Berry, Lisa Roesch, Martin Barnes, Arnima Bisht, Christian Rohlff, Keith Wilson, Dee Aud, Robert Boyd. The use of proteomics to analyse whole tumors and identify unique stroma cell targets for antibody-based therapeutics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 753.
Abstract 179: Blood Pressure Variability-Induced Aggravation of End-Organ Damages Is Another Achievable Target of Hypertension Treatment. -Effects of Angiotensin Receptor Blocker on an Animal Model-
Authors: Hiroshi Kudo, Hisashi Kai, Narimasa Takayama, Takahiro Mori, Yusuke Sugi, Daisuke Fukui, Kiyoko Kakemiya, Ayami Ikeda, Mitsuhisa Koga, Yoshitaka Hirooka, Tsutomu Imaizumi
Journal: Circulation (2007)
Abstract 5180: Bayesian multi-endpoint analysis of syngeneic mouse immunotherapeutic trials
Authors: David Gold, Ningning Chen
Journal: Cancer Research (2016)

Abstract Recent and notable immunotherapeutic successes for the treatments of melanoma and lung cancer have catalyzed wide-spread development of novel immunotherapies and combinations for a variety of cancers. While promising, responses to immunotherapies are a focal point of present investigations, being as of yet challenging to explain. Amongst the many translational challenges, pre-clinical in bred syngeneic mouse experiments often display heterogeneous tumor responses, whereby a fraction of tumors show resistance, partial, or complete response to the same immuno-intervention(s) implanted in identical in bred mouse strains. We mathematically modeled heterogeneous tumor responses in syngeneic mouse trials with Bayesian statistical methodology. Our decision criteria for drugs and drug combinations can simultaneously evaluate two or more endpoints. At the heart of our methodology is Bayesian learning with prior information that did not compromise statistical performance; actually, we achieved statistical gains to identify superior immunotherapies, rendering quantifiable efficiencies by design. We illustrate an augmented approach to discovery by Bayesian learning in real syngeneic mouse studies. We propose our powerful multi-endpoint Bayesian statistical criteria to ascertain superior pre-clinical immunotherapeutic activity. Citation Format: David Gold, Ningning Chen. Bayesian multi-endpoint analysis of syngeneic mouse immunotherapeutic trials. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5180.
Circulating cell-free DNA profiling of patients with advanced urothelial carcinoma.
Authors: Guru Sonpavde, Rebecca J Nagy, Andrea B. Apolo, Neeraj Agarwal, Sumanta K. Pal, Petros Grivas, Ulka N. Vaishampayan, Richard Burnham Lanman, AmirAli Talasaz
Journal: Journal of Clinical Oncology (2016)

358 Background: Urothelial carcinoma (UC) exhibits one of the highest somatic mutation burdens. Circulating cell-free DNA (cfDNA) is obtained non-invasively from peripheral blood and appears detectable in most patients (pts) with advanced UC. We report cfDNA profiling of patients with advanced UC using biopsy-free cfDNA sequencing. Methods: Twenty-nine patients with advanced UC that underwent cfDNA analysis using Guardant360 were identified. A 68-gene cfDNA next generation sequencing (NGS) panel from a CLIA-licensed, CAP-accredited laboratory (Guardant360) offers complete sequencing for all exons in 29 cancer associated genes, as well as the critical exons in 39 other genes, and copy number amplifications (16), fusions (4) and indels (1) in selected genes, harvested from 20 mL of peripheral blood. The mutant allele fraction (MAF) is defined as the number of mutated cfDNA molecules divided by the number wild type cfDNA molecules at a given nucleotide position. Results: Of 29 patients with advanced UC, cfDNA was detectable in 25 patients (86.2%). Twenty-nine patients were available with bladder primary in 27 pts (93.1%), and the median age was 75 years (range 52-91). The most common recurrent somatic mutations in the 25 patients with ≥ 1 alteration were in TP53 (n = 17), BRCA1/2 (n = 6), FGFR2 (n = 5), EGFR (n = 5), PIK3CA (n = 4), APC (n = 4), KRAS (n = 4), RAF1/BRAF (n = 4), and FGFR3, ALK, PDGFRA, NF1, CDKN2A and ARID1A were observed in 3 patients each. The most common genes with ≥ 2 copy numbers in the 25 evaluable patients were ERBB2 (n = 2) and PIK3CA, EGFR, RAF1, and FGFR1 in one patient each. Analysis of additional patients is ongoing in this expanding dataset. MAF data will be presented. Conclusions: cfDNA is frequently detected in patients with advanced UC, and alterations appear similar to those previously reported from UC tumor tissue. The correlation of cfDNA profiling with tumor tissue profiling within patients and ability to predict response requires study. Given that cfDNA offers a non-invasive means of profiling tumor DNA and MAF, further development of this promising modality is warranted to guide therapy with biologic agents and immunotherapy, and serial monitoring may provide insights regarding tumor biology.
Vascular Morphology Differences In Acute Myeloid Leukemia Are Associated with Blast Derived VEGFA Levels
Authors: Alida C. weidenaar, Ajra ter Elst, Gineke Koopmans-Klein, Stefano Rosati, Wilfred F.A. den Dunnen, Tiny G.J. Meeuwsen-de Boer, Willem A. Kamps, Edo Vellenga, Evelina S.J.M. de Bont
Journal: Blood (2010)
In Adult Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia, The Negative Prognostic Impact Of IKZF1, CDKN2A/B and PAX5 Deletions Is Not Abrogated By Allogeneic Stem Cell Transplantation In First Complete Remission
Authors: Heike Pfeifer, Katharina Raum, Sandra Markovic, Stephanie Fey, Julia Obländer, Verena Nowak, Wunderle Lydia, Fabian Lang, Dieter Hoelzer, Wolf-Karsten Hofmann, Nicola Goekbuget, Oliver G. Ottmann, Daniel Nowak
Journal: Blood (2013)
Preplanned initial safety analysis of ACTS-CC 02 trial: A large randomized phase III trial of SOX versus UFT/LV as adjuvant chemotherapy for high-risk stage III colon cancer.
Authors: Hiroya Takiuchi, Naohiro Tomita, Narikazu Boku, Toshiaki Watanabe, Kenjiro Kotake, Michio Itabashi, Keiichi Takahashi, Hideo Baba, Satoshi Morita, Kenichi Sugihara
Journal: Journal of Clinical Oncology (2012)

572 Background: The ACTS-CC 02 trial is designed to verify the superiority of postoperative adjuvant chemotherapy of S-1/Oxaliplatin (SOX) for patients with anyT, N2 colon cancer compared with UFT/Leucovorin (UFT/LV), which is one of standard adjuvant chemotherapies in Japan. To date, there have been no reported phase III trials evaluating SOX as postoperative adjuvant chemotherapy. This report presents initial safety data obtained from 50 patients who received SOX in the trial. Methods: Patients who underwent curative resection for anyT, N2 colon cancer were randomly assigned to receive either SOX (100 mg/m 2 of oxaliplatin on day1, and 80 to 120 mg/day according to body surface area (BSA) of S-1 on days 1-14, every 21 days, 8 courses) or UFT/LV (300 to 600 mg/day according to BSA of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 courses). Data were collected from initial consecutive 50 patients assigned to the SOX group and analyzed when they were considered evaluable for safety as planned in the protocol. This ongoing trial is designed to accrue 1200 patients. As of September 15, 2011, 319 patients have been accrued. Results: Of 50 patients assigned to receive SOX, 48 were evaluable for safety. The median number of treatment courses was 5 (range: 1-8). The relative dose intensity of S-1 was 83.8% and that of oxaliplatin was 86.6%. Grade 3 adverse events were neutropenia (14.6%), thrombocytopenia (2.1%), ALT elevation (2.1%), diarrhea (8.3%), fatigue (2.1%), and peripheral sensory neuropathy (2.1%). Grade 4 adverse effects were not observed. Conclusions: In this initial safety analysis, the incidence and severity of adverse events with SOX were acceptable in patients with high risk stage III colon cancer after curative resection. Enrollment of patients is ongoing.
An <i>In Vivo</i> Reporter to Quantitatively and Temporally Analyze the Effects of CDK4/6 Inhibitor-Based Therapies in Melanoma
Authors: Jessica L.F. Teh, Timothy J. Purwin, Evan J. Greenawalt, Inna Chervoneva, Allison Goldberg, Michael A. Davies, Andrew E. Aplin
Journal: Cancer Research (2016)

Aberrant cell-cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinases 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma. CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib, was recently FDA approved for the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF promote CDK4/6 activation, suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking. Here, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of antiapoptotic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts. These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma. Cancer Res; 76(18); 5455-66. ©2016 AACR.
Preparation, stability and pharmacokinetics evaluation of lipid microspheres loading a promising antitumor candidate, Timataxel
Authors: Yan Li, Haibing He, Qiao Wang, Xing Tang
Journal: Asian Journal of Pharmaceutical Sciences (2016)

Timataxel (13-(N-Boc-3-i-butylisoserinoyl-4,10-β-diacetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,13-α-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11-ene), used to be called TM-2, is a novel semi-synthetic promising candidate for cancer treatment. However the preformulation study showed that TM-2 was insoluble and chemically instable in water, which would limit its application. This study aimed at the preparation of Timataxel lipid microspheres (TM-2 LMs) and investigated the difference between TM-2 LMs and TM-2 solution in pharmacokinetics. In this work, the final formulation was as follows: 0.10% (w/v) TM-2; 10.00% (w/v) oil phase (long chain triglyceride:media chain triglyceride = 2.50%:7.50%); 1.40% (w/v) phospholipid; 0.02% (w/v) NaH2PO4; 2.25% (w/v) glycerin and water to a total volume of 100 ml. The particle size distribution, content and entrapment efficacy were 205.0 ± 43.3 nm, 101.00%, and 99.12%, respectively. TM-2 LMs were stable during storage at 25 °C for 3 months, even under the condition of 60 °C and 4500 lx for 10 d. Phosphatidylethanolamine (PE) in phospholipid may contribute to the stability of TM-2 LMs. The pharmacokinetic parameters for TM-2 LMs were as follows: AUC(0-∞) 3663.71 µg/l h and the clearance 2.26 l/h/kg. As for solution, these parameters were 1712.52 µg/l h and 4.77 l/h/kg, respectively. The t1/2 of TM-2 LMs was similar to TM-2 solution. The pharmacokinetic results indicated that the AUC of TM-2 LMs was larger, the clearance was smaller than that of TM-2 solution. In a word, lipid microspheres were a promising drug delivery system for TM-2.
Abstract 2186: Incorporation of natural compounds into biomaterials to prevent breast cancer recurrence
Authors: Lauren Jordan, Bailey-Jean Walker, Christopher Moody, Brian W. Booth
Journal: Cancer Research (2016)

Abstract Numerous studies have demonstrated that naturally occurring phytochemicals such as Tannic acid (TA) possess anti-cancer properties. Apoptotic activity is increased in breast cancer and prostate cancer cells in response to exposure to tannin extracts. Collagen type I is a biomaterial routinely used for cosmetic and reconstructive surgeries, including breast reconstruction following breast cancer mandated surgeries. TA functions as a collagen crosslinking agent through both hydrogen bonding and hydrophobic effects. Thus, if TA-crosslinked collagen type I is used for breast reconstruction procedures, the crosslinked collagen will be remodeled by growing breast epithelial cells and adipocytes where the incorporated TA will be released killing nearby residual cancer cells preventing recurrence. When adipocytes are grown on TA-crosslinked collagen beads the measureable released TA induces caspase-mediated apoptosis in ER+ and HER2+ breast cancer cells but has no effect on triple negative breast cancer cells and reduced apoptotic-inducing activity in normal breast epithelial cells. We are developing an injectable matrix comprised of TA-crosslinked collagen beads and adipocytes to serve as a tissue regeneration platform in patients post-lumpectomy. Variables such as collagen temperature, syringe pump rate, and drop distance have been studied to determine ideal method for producing beads of the desired size and shape. These promising results will lead to the construction of a matrix designed to not only promote tissue regeneration but also simultaneously help to prevent tumor recurrence. This matrix provides protection in breast cancer patients and holds promise for patients suffering from other soft tissue cancers. Citation Format: Lauren Jordan, Bailey-Jean Walker, Christopher Moody, Brian W. Booth. Incorporation of natural compounds into biomaterials to prevent breast cancer recurrence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2186.