tbuckley/cabot-search huggingface dataset:
Abstract SY30-04: Can protein discovery with complete molecular specificity increase return on investment for cancer biomarkers
Authors: Neil Kelleher
Journal: Cancer Research (2015)

Abstract Bottom-up proteomics relies on the use of proteases and is the method of choice for identifying thousands of protein groups in complex samples. Top-down proteomics has been shown to be robust for direct analysis of small proteins and offers a solution to the “peptide-to-protein” inference problem inherent with bottom-up. This talk will focus on the results in our recently accepted manuscript which describes the first large-scale integration of genomic, bottom-up and top-down proteomic data for comparative analysis of patient-derived mouse xenograft models of basal and luminal B human breast cancer, WHIM2 and WHIM16, respectively. Using these well-characterized xenograft models established by the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium, we compared and contrasted the performance of bottom-up and top-down proteomics to detect cancer-specific aberrations at the peptide and proteoform levels, and to measure differential expression of proteins and proteoforms. For proteins in the range of 0-30 kDa, bottom-up proteomics quantified 3,519 protein groups from 49,185 peptides, while top-down proteomics quantified 982 proteoforms mapping to 358 proteins. Examples of both concordant and discordant quantitation were found in an approximately 60:40 ratio, providing a unique opportunity for top-down to fill in missing information. The two techniques showed complementary performance, with bottom-up yielding 8 times more identifications of 0-30 kDa proteins in xenograft proteomes, but failing to detect differences in post-translational modifications, such as phosphorylation pattern changes of alpha-endosulfine. This initial study illustrates the potency of a combined bottom-up and top-down proteomics approach to deepen our knowledge of cancer biology, especially when genomic data are available. Citation Format: Neil Kelleher. Can protein discovery with complete molecular specificity increase return on investment for cancer biomarkers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY30-04. doi:10.1158/1538-7445.AM2015-SY30-04
Dendritic cell (DC) vaccination with low dose temozolomide phase I/II trial in melanoma patients: Preliminary data on peripheral blood regulatory t-cells (Treg) and DC-TEM8 expression modulations.
Authors: M. Petrini, L. Ridolfi, L. Fiammenghi, M. Napolitano, A. M. Granato, V. Ancarani, E. Pancisi, M. Guidoboni, S. Nicoletti, L. Valmorri, A. Riccobon, G. Migliori, F. M. Venanzi, P. A. Ascierto, R. Ridolfi
Journal: Journal of Clinical Oncology (2011)

e13029 Background: Cytolytic T lymphocytes (CTL) able to kill tumor cells are efficiently induced by Dendritic Cells (DC); however, immunosuppressive factors, as CD4+CD25+FoxP3+ T lymphocytes (T-reg) and TEM8 expression by DC, hamper efficient activation. After our experience of a vaccination trial using autologous mature DC (mDC) pulsed with autologous tumor lysate (ATL) and Keyhole Limpet Hemocyanin (KLH), in 2007 we started a phase I/II study with low-doses temozolomide (ldTMZ, given by Schering Plough Italy) before the vaccine in metastatic melanoma patients. Methods: TMZ 75mg/m2/day (maximum total dose 100mg/day) for 14 days (-14 to -1), DC Vaccination (day 0), and IL-2 3MUI/day s.c (days 2-5) q every 2 weeks for the first 4 vaccine and then monthly. Clinical and radiological evaluation as well as Delayed-type hypersensitivity (DTH) test for in vivo immunomonitoring were performed at basal and every 4 vaccinations. Circulating T-reg were evaluated at day -14, 0 and after IL-2. TEM8 expression in mDC (TEM8 mRNA ratio mDC vs immature DC) was investigated in 5 non progressing patients (NP) and in 7 progressing patients (PD) by QRT-PCR. Results: Up to September 2010, 17 patients were treated (5 females and 12 males, median age 57 years). Out of 15 evaluable patients 1 showed partial response (PR) of 6 months, 6 stable disease (SD) of 4,4,4,9,9,10 months and 8 progressed (PD), without major toxicities. All responders had positive DTH test, although weak in 1 patient with SD and in 3 patients with PD. TEM8 mRNA levels increased after iDC maturation, but no significant difference was found in mDC TEM8 expression mean fluorescence intensity between NP and PD. The absolute number of Treg (evaluated in 12 patients) decreased after TMZ treatment in 4 of the 6 PD patients and in all NP patients; however, after IL-2 administration, all patients except 4 of the 7 NP showed a rebound peak of Treg. Conclusions: These preliminary data suggest that ldTMZ may down-modulate T-reg population. Further investigations are needed to understand the role of T-reg and their relatively low growth after IL-2 administrations in NP patients.
Abstract 5319: Apoptotic properties of platinum antitumor agents phosphaplatins
Authors: Homa Dezvareh
Journal: Cancer Research (2015)

Abstract Phosphaplatins, a group of non-DNA binding platinum compounds, exhibit excellent in vivo and in vitro efficacies against a variety of cisplatin- and carboplatin-sensitive and resistant ovarian cancers. Although, combinations of cis- or carbo-platin and paclitaxel therapies continue to be the choice of treatment for many ovarian cancer patients, many develop resistance to treatment. Phosphaplatins are pyrophosphate bound platinum-(II) and (IV)-platinum complexes that bi-negatively charged at or near neutral pH. Both Platinum (II) and platinum (IV) complexes did not overexpress any DNA repair genes consistent with the no-DNA binding property of phosphaplatins. In this report, we show the apoptotic properties of two representative compounds, (R,R-1,2-cyclohexanediamine)-(dihydrogen pyrophosphato)platinum (II) (RRD2) and (R,R-1,2-cyclohexanediamine)-trans-dihydroxo(dihydrogen pyrophosphato)platinum (IV) (RRD4) through a variety of experiments as described below. Phosphaplatins activate and upregulate death receptors on cell surface such as FAS, DR5, and TNFR1. These three death receptors follow the common signaling path to trigger apoptosis by an extrinsic pathway via Death Inducing Signaling Complex (DISC) by recruiting FADD and procaspase-8 and activating caspase-8. A direct binding of FAS by platinum is implicated as the platinum compound was found to be co-localized in the lipid rafts. The PTEN-PI3K pathway involvement was confirmed by the down regulation of both PI3K and p-AKT. Phosphoplatins also upregulate tumor suppression genes P53 and PTEN. Apoptosis by p53 signaling follows intrinsic pathways involving BCL-proteins. In particular up regulation of BAX, PUMA, and downregulation of BCL2 were observed. To further confirm p53-signailng, we have identified a number of p53 target genes that include AEN, CYFIP2, TP53I3, TP53INP1, DPYSL4, LRDD, DRAM1, and a few others. Our data shows that phosphaplatins have the potential to not only treat resistant but also advanced metastatic ovarian cancers. Citation Format: Homa Dezvareh. Apoptotic properties of platinum antitumor agents phosphaplatins. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5319. doi:10.1158/1538-7445.AM2015-5319
Population pharmacokinetic analysis from phase I and phase II studies of the humanized monovalent antibody, MetMAb, in patients with advanced solid tumors.
Authors: S. Bai, Y. Xin, D. Jin, S. Kaur, I. Nijem, J. G. Bothos, A. C. Peterson, P. H. Patel
Journal: Journal of Clinical Oncology (2011)

2571 Background: MetMAb is a recombinant, humanized, monovalent monoclonal antibody directed against the tyrosine kinase Met, based on the human IgG (k) framework sequences, and is the first monovalent antibody in clinical development. The unique monovalent design of MetMAb reduces the potential for Met activation, found with bivalent anti-Met antibodies. The main objective of the analyses was to characterize the pharmacokinetics (PK) of MetMAb. Methods: MetMAb was administered intravenously once every 3 weeks (q3wk). The noncompartment and population PK analyses were performed using patient data from a Phase I dose escalation study (1, 4, 10, 20, 30 mg/kg as a single agent, 10 and 15 mg/kg with bevacizumab (bev) 15 mg/kg q3wk) and a Phase II study in 2nd/3rd line NSCLC patients (15 mg/kg q3wk with erlotinib 150 mg daily). Potential PK drug-drug interaction (DDI) was assessed for coadministration of MetMAb with bev or erlotinib. Results: MetMAb showed linear PK in the dose range of 4-30 mg/kg. The clearance (CL) was faster (~2-fold) at 1 mg/kg compared with the other dose groups, suggesting that the target-mediated CL pathway played a major role at the low dose. In the linear-dose range, the mean CL values were in the range of 6.8-9.9 mL/day/kg, about 1.5- to 2-fold faster than the range reported for typical bivalent IgG antibodies. The mean elimination half-life is in the range of 8-12 days. In the Phase II study, over 90% patients achieved the target steady state trough concentrations (i.e., 15 ug/mL based on preclinical studies) with the mean value of about 73 ug/mL. Cross-study comparison did not show significant PK DDI for MetMAb in combination with bev or erlotinib. Although minimal and transient anti-therapeutic antibody (ATA) responses were detected in 7 out of 98 MetMAb-treated patients, the MetMAb PK profiles did not appear to be impacted in the ATA-positive patients. Conclusions: This is the first report of monovalent antibody PK from Phase I and II studies. Although slightly faster CL and shorter half-life were observed compared with typical bivalent antibodies, the PK profile supports q2wk or q3wk dosing regimens to achieve an effective and safe exposure in patients.
Abstract LB-080: Reactivating RBL2/p130 oncosuppressive function as a new, possible antitumoral strategy
Authors: Francesca Pentimalli, Luca Esposito, Iris Maria Forte, Carmelina Antonella Iannuzzi, Flavio Rizzolio, Tiziano Tuccinardi, Paola Indovina, Silvia Boffo, Antonio Giordano
Journal: Cancer Research (2015)

Abstract Deregulation of cell cycle control is the leading cause of cancer. The retinoblastoma (Rb) family members, including RB1/p105, RBL1/p107 and RBL2/p130, are crucial to restrain cell cycle progression and their inactivation, either direct or indirect, is a hallmark of most human tumors. In particular, RBL2/p130 emerging role in senescence and apoptosis, seems to contribute importantly to its tumor suppressor function. Furthermore, many studies largely contributed to establish RBL2/p130 as an important cancer target, which is inactivated by cell cycle kinases and whose deregulation underlies various cancer types. In this regard, we set out to restore RBL2/p130 function in tumors and exploit its tumor suppressive potential for cancer therapy. In particular, we have identified, through computational chemistry and molecular modeling studies, a small molecule able to act as a specific inhibitor of the CDK2-CycA complex and to reactivate the tumor suppressive function of RBL2/p130 in cancer. We analyzed by MTS assay the cytotoxic effect of our compound on a panel of different tumor cell lines and determined its IC50 values. We evaluated its effects on cell cycle and apoptosis by FACS and dissected its molecular mechanism of action by Western blot and RT-PCR. We found that our compound effectively inhibited proliferation of lung cancer and mesothelioma cell lines by specifically inhibiting CDK2-CycA activity towards RBL2/p130. The decrease in RBL2/p130 phosphorylation led to stabilization of its complex with the E2F4 transcriptional factor and consequent repression of their targets necessary for cell cycle progression, including CDK2 itself. Consistently, our compound arrested cell cycle and triggered apoptosis. Interestingly, apoptosis seemed to be mediated by RBL2/p130 itself because it was repressed in RBL2/p130-silenced cells. Furthermore, our compound proved to be active in an A549 xenograft model of lung cancer. Overall our findings indicate that the pharmacological reactivation of RBL2/p130 induces its cell-cycle restraining and pro-apoptotic functions, the latter being still largely unexplored, and identify a new possible therapeutic strategy for cancer treatment. Citation Format: Francesca Pentimalli, Luca Esposito, Iris Maria Forte, Carmelina Antonella Iannuzzi, Flavio Rizzolio, Tiziano Tuccinardi, Paola Indovina, Silvia Boffo, Antonio Giordano. Reactivating RBL2/p130 oncosuppressive function as a new, possible antitumoral strategy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-080. doi:10.1158/1538-7445.AM2015-LB-080
60. Intramuscular and Systemic Induction of the N-Truncated Dystrophin By Out-Of-Frame Exon 2 Skipping Restores Muscle Function in the Dup2 Mouse, Providing Further Support for a Therapeutic Pathway for 5’ DMD Mutations
Authors: Nicolas Wein, Adeline Vulin, Tabatha Simmons, Felecia Gumienny, Nianyuan Huang, Francesco Muntoni, James Ervasti, Robert Weiss, Kevin Flanigan
Journal: Molecular Therapy (2015)

Most mutations that truncate the reading frame of the DMD gene result in loss of dystrophin expression and lead the severe Duchenne muscular dystrophy. However, frame-truncating mutations within the first five exons of DMD result in mild dystrophinopathy with expression of a N-truncated dystrophin. We have recently shown that this is due to activation of an internal ribosome entry site (IRES) within exon 5 resulting in translation from an exon 6 AUG codon. We demonstrated that this IRES is active in patients expressing the N-truncated dystrophin, raising the possibility of the therapeutic use of this isoform. To explore this we developed a novel out-of-frame exon-skipping approach that uses AAV-mediated U7snRNA to efficiently skip exon 2. By injecting this AAV vector into a DMD mouse model carrying a duplication of exon 2 (Dup2), this generates a truncated reading frame, leading to activation of the IRES and synthesis of the N-truncated isoform. We now demonstrate that despite lacking the first half of the canonical actin binding domain 1, this N-truncated protein is highly functional. Intramuscular injection of the AAV1.U7snRNA vector into Dup2 mice results in high levels of expression of the N-truncated isoform by 4 to 6 weeks post-injection, along with complete correction of the physiologic and pathologic features as measured by Evans blue dye uptake, hindlimb grip strength, tibialis anterior specific force, and force correction after eccentric contraction. Preliminary results supports that systemic delivery of AAV9.U7snRNA vector into Dup2 mice induce expression of this functional isoform into all muscle including heart and diaphragm, thereby improving muscle histopathology. Following treatment, a genome-wide normalized RPF-Seq data analysis (Ribosome Protected Fragment) was performed to check if the treatment restored the Haslett gene lists (gene altered in DMD) to a 'non-dystrophic' pattern. Our data clearly indicates that the treatment restored the global expression pattern to a more normal pattern. This level of correction to that of control mice supports the idea that this novel therapeutic approach should be beneficial for the 6% of patients with mutations within the first five exons of DMD.
Functional outcome of malignant spinal cord compression treated with radiotherapy alone: A prospective analysis
Authors: S. Spensley, J. A. Gilmore, J. Kenny, M. Dunne, A. Clayton-Lea, P. G. Thirion
Journal: Journal of Clinical Oncology (2009)

e20623 Background: Malignant spinal cord compression (MSCC) is a major oncological complication. The management of Impending Malignant Spinal Cord Compression (IMSCC) remains unclear. Radiotherapy (RT) is often the sole management of both entities. Our aim was to prospectively evaluate the functional outcome of MSCC and IMSCC. Methods: All pts with MSCC and IMSCC treated by RT in our institution were screened for 2 national trials (ICORG 05–03/07–11). Non-eligible pts were prospectively evaluated and followed with assessment of mobility (modified Tomita scale) and sphincter function (continence/ incontinence/catheter) at baseline and 5 weeks posttreatment. Results: From 08/07 to 11/08, 54 pts [23 IMSCC, 31 MSCC] were followed. 31 pts were male. The median age was 60.5 y (30–86). The primary tumours were haematological [13 pts], lung [10], prostate [8], renal cell [6] and breast [5]. 51 pts had diagnostic MRI. The compression level was cervical in 6 pts, thoracic in 27, lumbosacral in 16, and 5 had multiple levels. 2D RT was used with varying radiation schedules: 20Gy/5fractions (f) [32 pts], 30Gy/10f [12] and other [10]. At baseline, normal mobility was found in 29 pts, mildly impaired mobility in 15 and immobility in 10. 7 pts had sphincter dysfunction. At 5 weeks, 38 pts (16 IMSCC, 22 MSCC) were evaluable (37 for mobility score, 38 for sphincter function). 10 pts had died and 6 were lost to follow up. Overall mobility was stable, improved or worse in 28 pts, 3 pts and 6 pts respectively. The mobility score was worse in 4 pts with IMSCC and 2 pts with MSCC. Improvement of mobility score was seen in 2 pts with MSCC. Among the 7 pts with baseline sphincter dysfunction, 2 pts improved. New sphincter dysfunction after RT was seen in 2 pts with IMSCC. Conclusions: The functional outcome of MSCC treated by RT alone remains poor, with minimal mobility and sphincter improvement. Functional outcome of pts with IMSCC is worrying with a worsening of mobility and/or occurrence of sphincter dysfunction in a large number of patients. No significant financial relationships to disclose.
Allograft T Cell Content Influences Early Engraftment after Reduced-Intensity Stem Cell Transplantation (RIST).
Authors: Robert M. Dean, Daniel H. Fowler, Nancy M. Hardy, Jeanne Odom, Kathleen Castro, Michael Krumlauf, Frances T. Hakim, Claude Sportes, Ronald E. Gress, Michael R. Bishop
Journal: Blood (2005)
Ofatumumab, a Fully Human Monoclonal Antibody Targeting CD20, Demonstrates Activity Against and Potentiates the Anti-Tumor Activity of Chemotherapy Agents In Rituximab-Sensitive Cell Lines (RSCL), Rituximab-Resistant Cell Lines (RRCL), Lymphoma Xenografts, and Primary Tumor Cells Derived From Patients with B-Cell Non-Hodgkin Lymphoma (NHL)
Authors: Matthew Barth, Francisco J. Hernandez-Ilizaliturri, Cory Mavis, Ping-Chiao Tsai, John Gibbs, George Deeb, Myron S. Czuczman
Journal: Blood (2010)
Final results of a phase I study of the combination of a novel cell cycle inhibitor ON 01910.Na with gemcitabine in patients with advanced pancreatic and other solid tumors.
Authors: W. W. Ma, W. A. Messersmith, G. K. Dy, E. Freas, A. Whitworth, F. Wilhelm, S. G. Eckhardt, A. A. Adjei, A. Jimeno
Journal: Journal of Clinical Oncology (2011)

3101 Background: ON 01910.Na (ON) is a novel multitargeted inhibitor of several regulatory pathways including polo-like kinase 1 (Plk1) and PI-3 kinases, with synergistic preclinical activity when combined with gemcitabine (G; Jimeno et al, 2008, 2009), prompting a phase I clinical evaluation. Methods: Patients (pts) had histologically confirmed solid tumors refractory to standard therapy. G was administered as a 30-min infusion on days 1, 8 and 15 of a 28-day cycle. ON was administered as a 2-h infusion on days 1, 4, 8, 11, 15, and 18. Assessments included safety, response, pharmacokinetic interaction studies at the MTD, and pharmacodynamics in tumor at the MTD. The MTD was further confirmed in an expansion cohort enriched in advanced pancreatic cancer pts. Results: Thirty-six pts (median age 61; median ECOG PS 1) received a median of 3 cycles (6 pts ongoing) at 5 dose levels: (G/ON mg/m2: 750/600 n=6; 1,000/600 n=5; 750/1,200 n=3; 1,000/1,200 n=3; 1,000/1,800 n=19). Only those toxicities that were expected from G were observed in patients treated with the combination, and included thrombocytopenia, neutropenia, elevated AST/ALT, nausea, vomiting, and fatigue. One DLT was documented (death at Day 18 at the 1,800 mg/m2 ON dose). Antitumor activity was seen in one G-pretreated Hodgkin lymphoma pt (PR), 2 ovarian cancer pts (1 G-pretreated with 50% decrease in CA125; 1 G-naïve with 50% decrease in CA125 and 12% tumor regression), one NSCLC pt (SD at 24 weeks) and one thymic cancer pt (PR at 32 weeks). Additionally, 18 advanced pancreatic cancer (PC) pts were enrolled. Tumor regression (including one confirmed PR in a G-pretreated pt) was noted in 7/13 evaluable pts and CA 19-9 decrease in 8/13 pts. Median progression-free survival was 19 weeks and overall survival 48 weeks at 1,200 and 1,800 mg/m2 ON doses (n=12) in the subset of 16 metastatic PC pts, 11 of whom were previously treated with G. Conclusions: ON 01910.Na 1,800 mg/m2 and gemcitabine combination is well tolerated. Anti-tumor activity in G-pretreated pts with advanced PC provide the rationale for a phase II evaluation in metastatic PC pts. Final results will be presented and molecular data including PI3K mutation status.
Health resource utilization (HRU) associated with skeletal-related events (SREs) in patients with bone metastases (BM): Results of a prospective multinational observational study.
Authors: A. Bahl, H. Hoefeler, I. Duran, G. Hechmati, C. Garzon-Rodriguez, D. Lueftner, J. Ashcroft, R. Wei, E. Thomas, V. Lorusso
Journal: Journal of Clinical Oncology (2011)

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418. Peripheral Blood Leucocytes, Neutralizing Antibodies and Tumor Burden as Predictive and Prognostic Factors in Patients Treated with Oncolytic Adenoviral Immunotherapy
Authors: Suvi Parviainen, Kristian Taipale, Ilkka Liikanen, Anniina Koski, Anna Kanerva, Minna Oksanen, Akseli Hemminki
Journal: Molecular Therapy (2016)

Oncolytic immunotherapy has taken significant steps towards clinical availability for cancer patients, as the FDA recently approved Imlygic (T-Vec) for the treatment of melanoma. Despite the several oncolytic virus trials, there are no known biomarkers which could predict the treatment outcome of oncolytic virotherapy. Therefore, previous clinical experiences should be utilized as guidance for further treatment optimization and patient selection. The patients analyzed consisted of 246 patients treated with oncolytic adenovirus as a part of the Advanced Therapy Access Program which was ongoing in Helsinki 2007-2012. Taken together with the increasing understanding that immunological factors might determine the efficacy of oncolytic virotherapy, we studied whether neutralizing antibodies and peripheral blood cell counts would have prognostic and/or predictive significance in the context of oncolytic adenovirus treatments. Additionally, tumor burden was assessed both in terms of primary tumor and metastases. We observed presence of neutralizing antibodies before treatment to be correlated with shorter overall survival (p=0.028). Blood cell counts analyses revealed that patients who had high neutrophil to lymphocyte ratio at baseline had significantly shorter overall survival (p<0.001). After treatment patients demonstrated transient lymphopenia and increases in neutrophils, which varied between disease control and progressive disease groups. Patients with high total tumor load had significantly shorter overall survival compared to low tumor load group (p=0.003). Interestingly, we also found presence of liver metastases to be correlated with reduced rate of disease control (p=0.021). These data indicate possible reasons behind the nonuniform treatment outcomes frequently observed after virotherapy. Moreover, our results suggest potential approaches for treatment refinement and patient selection in the context of oncolytic immunotherapy. Given the similarity of biological effects seen with different oncolytic DNA viruses, it will be interesting to see if these results will be similar in the context of other oncolytic viruses and cancer immunotherapy approaches such as adoptive T-cell therapy and cancer vaccines.