tbuckley/cabot-search huggingface dataset:
751. Improving CAR T Cell Function by Reversing the Immunosuppressive Tumor Environment of Pancreatic Cancer
Authors: Sujita Sukumaran, Somala Mohammed, Norihiro Watanabe, Pradip Bajgain, Salma Ansari, Usanarat Anurathapan, Helen E. Heslop, Cliona R. Rooney, Malcolm K. Brenner, Ann M. Leen, Juan F. Vera
Journal: Molecular Therapy (2016)

Adoptive transfer of T cells redirected to tumor-associated antigens (TAAs) by expression of chimeric antigen receptors (CARs) can produce tumor responses, even in patients with resistant malignancies. To target pancreatic ductal adenocarcinoma (PDAC), we generated T cells expressing a CAR directed to the TAA prostate stem cell antigen (PSCA). T cells expressing this CAR were able to kill PSCA(+) tumor cell lines CAPAN1 and K562-PSCA but not PSCA(-)293T cells (74±4%, 73±6% and 9±3% specific lysis, respectively, 10:1 E:T, n=3). Although these CAR-T cells had potent anti-tumor activity, pancreatic tumors employ immune evasion strategies such as the production of inhibitory cytokines, which limit in vivo CAR-T cell persistence and effector function. Indeed, when we examined the serum of patients with pancreatic cancer (n=8) we found the levels of the immunosuppressive cytokine IL4 to be elevated relative to patients with benign pancreatic disorders or normal healthy controls (14.25±19.48 pg/mL vs 7.28±9.03 vs 1.13±1.42 pg/mL). Thus, to protect our CAR-PSCA T cells from the negative influences of IL-4, we generated a chimeric cytokine receptor in which the IL4 receptor exodomain was fused to the IL7 receptor endodomain (IL4/7 ChR). Transgenic expression of this molecule in CAR-PSCA T cells can invert the inhibitory effects of tumor-derived IL4 to instead promote the proliferation of the effector CAR T cells. In preliminary experiments, we successfully co-expressed both CAR-PSCA and IL4/7 ChR (47.5±12.3% double-positive cells, n=4) on primary T cells. These T cells retained their tumor-specific activity (80±8% specific lysis against CAPAN1, 10:1 E:T, n=3) and when cultured in conditions that mimic the tumor milieu (IL4 12.5 ng/ml), CAR-PSCA 4/7R ChR-modified T cells continued to expand (increase from 2×10e6 cells on day 0 to 5.53±8.46×10e10 cells on day 28), unlike unmodified CAR-PSCA T cells which plateaued at 3.84±5.43×10e8 cells (n=4). Indeed, in the presence of IL4, transgenic cells had a selective advantage (comprising 44.8±11.0% of the population on day 0 and 87.6±10.0% on day 28; n=4). However, even after prolonged cytokine exposure these T cells remained both antigen- and cytokine-dependent. In conclusion, CAR-PSCA 4/7 ChR-modified tumor-specific T cells can effectively target pancreatic cancer cells and are equipped to expand, persist, and retain their cytotoxic function even in the presence of high levels of IL4 in the tumor microenvironment.
Abstract 2030: FRK regulates glioma cell progression by promoting N-cadherin/β-catenin complex formation
Authors: Qiong Shi, Xu Song, Haoping Yan, Jun Wang, Weijian Zhang, Jinxia Hu, Xiuping Zhou, Rutong Yu
Journal: Cancer Research (2015)

Abstract Fyn-related kinase (FRK), a member of Src-related tyrosine kinases, is recently reported to function as a potent tumor suppressor in several cancer types. Our previous studies has also shown that FRK over-expression inhibited the migration/invasion, proliferation and promoted apoptosis of glioma cells. However, the mechanism of FRK on glioma cell migration/invasion, proliferation and apoptosis is still not clear. In this study, we found that FRK over-expression increased the protein level of N-cadherin, but not that of E-cadherin. Meanwhile, FRK over-expression promoted β-catenin translocation to the plasma membrane, where it formed complex with N-cadherin, while inhibited β-catenin translocation to the nucleus. In addition, down-regulation of N-cadherin by siRNA promoted the migration/ invasion proliferation and inhibited apoptosis of glioma U251 and U87 cells. Interestingly, N-cadherin down-regulation abolished the effect of FRK on glioma cell migration/invasion, proliferation and apoptosis. In summary, these results indicate that FRK regulates glioma cell progression by promoting N-cadherin/β-catenin complex formation. Citation Format: Qiong Shi, Xu Song, Haoping Yan, Jun Wang, Weijian Zhang, Jinxia Hu, Xiuping Zhou, Rutong Yu. FRK regulates glioma cell progression by promoting N-cadherin/β-catenin complex formation. [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 2030. doi:10.1158/1538-7445.AM2015-2030
Abstract 4824: Pancreatic adenocarcinoma: Comparative analysis of cancer stem cell markers between neoadjuvant and treatment naïve specimens
Authors: Whitney Horsley, Melissa Stanley, Bert O'Neil, Safi Shahda, George Sandusky
Journal: Cancer Research (2015)

Abstract To better understand the effect of neoadjuvant therapy on the presence of stem cell within pancreatic adenocarcinoma, CD24 and ALDH1 expression levels were compared between surgical specimens that received neoadjuvant therapy and those that did not. ALDH1+ and CD24+ cells have been implicated as markers for cancer stem cells in various cancers. For this study, paraffin-embedded tissues slides were obtain from Indiana University Simon Cancer Center Tissue Procurement and Indiana University Health Pathology Laboratory under approved IRB protocols. The tissues were then stained with immunohistochemical stains for CD24 and ALDH1, scanned using Aperio Imaging System and analyzed using the positive-pixel algorithm in ImageScope giving a percentage of tumor tissue expressing each marker. The results showed that the neoadjuvant tissues (avg. 42.1%) expressed a higher level of ALDH1 (p&amp;lt;0.001) than the treatment naïve tissue (avg. 24.9%); and that the treatment naïve tissues (avg. 30.1%) expressed a higher level of CD24 (p = 0.01) than the neoadjuvant tissue (avg. 17.9%). This indicates that neoadjuvant therapy may be effectively eliminating non-stem cells but not as effective at targeting stem cells expressing ALDH1, though somewhat effective at targeting CD24+ cells. Citation Format: Whitney Horsley, Melissa Stanley, Bert O'Neil, Safi Shahda, George Sandusky. Pancreatic adenocarcinoma: Comparative analysis of cancer stem cell markers between neoadjuvant and treatment naïve specimens. [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 4824. doi:10.1158/1538-7445.AM2015-4824
Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors
Authors: Jonathon Torchia, Brian Golbourn, Shengrui Feng, King Ching Ho, Patrick Sin-Chan, Alexandre Vasiljevic, Joseph D. Norman, Paul Guilhamon, Livia Garzia, Natalia R. Agamez, Mei Lu, Tiffany S. Chan, Daniel Picard, Pasqualino de Antonellis, Dong-Anh Khuong-Quang, Aline C. Planello, Constanze Zeller, Dalia Barsyte-Lovejoy, Lucie Lafay-Cousin, Louis Letourneau, Mathieu Bourgey, Man Yu, Deena M.A. Gendoo, Misko Dzamba, Mark Barszczyk, Tiago Medina, Alexandra N. Riemenschneider, A. Sorana Morrissy, Young-Shin Ra, Vijay Ramaswamy, Marc Remke, Christopher P. Dunham, Stephen Yip, Ho-keung Ng, Jian-Qiang Lu, Vivek Mehta, Steffen Albrecht, Jose Pimentel, Jennifer A. Chan, Gino R. Somers, Claudia C. Faria, Lucia Roque, Maryam Fouladi, Lindsey M. Hoffman, Andrew S. Moore, Yin Wang, Seung Ah Choi, Jordan R. Hansford, Daniel Catchpoole, Diane K. Birks, Nicholas K. Foreman, Doug Strother, Almos Klekner, Laszló Bognár, Miklós Garami, Péter Hauser, Tibor Hortobágyi, Beverly Wilson, Juliette Hukin, Anne-Sophie Carret, Timothy E. Van Meter, Eugene I. Hwang, Amar Gajjar, Shih-Hwa Chiou, Hideo Nakamura, Helen Toledano, Iris Fried, Daniel Fults, Takafumi Wataya, Chris Fryer, David D. Eisenstat, Katrin Scheinemann, Adam J. Fleming, Donna L. Johnston, Jean Michaud, Shayna Zelcer, Robert Hammond, Samina Afzal, David A. Ramsay, Nongnuch Sirachainan, Suradej Hongeng, Noppadol Larbcharoensub, Richard G. Grundy, Rishi R. Lulla, Jason R. Fangusaro, Harriet Druker, Ute Bartels, Ronald Grant, David Malkin, C. Jane McGlade, Theodore Nicolaides, Tarik Tihan, Joanna Phillips, Jacek Majewski, Alexandre Montpetit, Guillaume Bourque, Gary D. Bader, Alyssa T. Reddy, G. Yancey Gillespie, Monika Warmuth-Metz, Stefan Rutkowski, Uri Tabori, Mathieu Lupien, Michael Brudno, Ulrich Schüller, Torsten Pietsch, Alexander R. Judkins, Cynthia E. Hawkins, Eric Bouffet, Seung-Ki Kim, Peter B. Dirks, Michael D. Taylor, Anat Erdreich-Epstein, Cheryl H. Arrowsmith, Daniel D. De Carvalho, James T. Rutka, Nada Jabado, Annie Huang
Journal: Cancer Cell (2016)
Abstract 3203: Multiple myeloma microenvironment and obesity
Authors: Erica Bullwinkle
Journal: Cancer Research (2015)

Abstract Multiple myeloma accounts for roughly 1% of all cancers diagnosed in the United States each year. Risk factors include environmental exposure, age, ancestry, gender, and obesity. Rates of obesity are on the rise in the United States and around the world; in the United States alone, 69% of adults are either overweight (BMI 25-30) or obese (BMI 30-35) and 6.3% of adults are extremely obese (BMI &amp;gt; 35). Although there is a strong epidemiological correlation between obesity and multiple myeloma, the mechanism by which adipocytes contribute to the development and progression of the cancer has yet to be identified. In this study, we isolated stem cells from patients undergoing elective liposuction surgery, differentiated the stem cells into adipocytes, and co-cultured the adipocytes with RPMI 8226 or NCI-H929 multiple myeloma (MM) cell lines. MM cells proliferated faster when co-cultured with adipocytes versus growing alone. MM growth rate was significantly higher in response to adipocytes from obese patients in comparison to adipocytes from normal weight individuals. Further, conditioned media from adipocytes from obese patients significantly increased pro-angiogenic signaling within a tube formation assay, induced an increase in MM cell adhesion, and increased expression of matrix metalloproteinases. In summary, our data suggests that adipocytes in the MM microenvironment contribute to MM progression and should be further evaluated as a possible therapeutic target. Citation Format: Erica Bullwinkle. Multiple myeloma microenvironment and obesity. [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 3203. doi:10.1158/1538-7445.AM2015-3203
Angelina Jolie’s mastectomy triggered sharp rise in gene testing
Authors: Zosia Kmietowicz
Journal: BMJ (2016)

A 2013 announcement by the actor Angelina Jolie that she had had a mastectomy led to a sharp increase in breast cancer gene testing in US women but no change in overall mastectomy rates, a study in the Christmas issue of The BMJ has found.1

The results suggested that celebrity announcements influence the use of healthcare services but do not effectively target the groups at greatest risk for the underlying condition, said the researchers. Celebrity endorsements of health issues such as screening, fad diets, and supplements are ubiquitous—but evidence that they affect …
Abstract 5005: Androgen-mediated genomic and non-genomic regulation of TRPM8 in prostate cancer
Authors: Swapna Asuthkar, Eleonora Zakharian
Journal: Cancer Research (2015)

Abstract Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing and Ca2+ permeable channel protein. The TRPM8 mRNA is overexpressed in early prostate tumors with high androgen levels, while anti-androgen therapy greatly reduces its expression. Thus, androgens, which are at the crossroads of several signaling pathways, appear to be associated with TRPM8-mediated Ca2+ -dependent signaling. Genomic regulation; From the chromatin-immunoprecipitation (ChIP) analysis, we observed that an androgen response element (ARE) mediates androgen regulation of trpm8. Although TRPM8 mRNA is expressed at high levels in prostate cancer (PC) cells, we found that the TRPM8 protein undergoes UBA1-mediated ubiquitination and degradation. PYR-41, a potent inhibitor of initial enzyme in the ubiquitination cascade, UBA1 increased TRPM8 activity on the plasma membrane of LNCaP cells. Further, PYR-41-mediated PMTRPM8 activity was accompanied by enhanced activation of p53 and Caspase-9. In addition, we found that the promoter region of trpm8 possesses putative binding sites for p53 and that the overexpression of p53 increased the TRPM8 mRNA levels. Our findings support previous studies that suggest the fine balance between androgen receptor (AR) and p53 expression that regulates androgen-dependent growth of PC. Non-genomic regulation; Furthermore, using immunofluorescence, calcium-imaging and planar lipid bilayers, we identified that TRPM8 channel is functionally associated with androgens in the prostate. Most importantly, we report that testosterone can directly activate TRPM8 channel at low picomolar concentrations and resulted in full openings of the purified TRPM8 channel in planar lipid bilayers. Our data demonstrated that testosterone is an endogenous and highly potent agonist of TRPM8 channel. In light of these observations our data of non-genomic effect of testosterone on PMTRPM8 may support a strategy for targeting the androgen-TRPM8-AR interaction or rescuing PMTRPM8 expression as a new therapeutic application for PC. Note: This abstract was not presented at the meeting. Citation Format: Swapna Asuthkar, Eleonora Zakharian. Androgen-mediated genomic and non-genomic regulation of TRPM8 in prostate cancer. [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 5005. doi:10.1158/1538-7445.AM2015-5005
A Multi-Center, Non-Randomized Phase 2 Study of Ofatumumab in Combination with ICE-Chemotherapy (O-ICE) in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Tiffany Tang, Cindy Lim, Miriam Tao, Richard Quek, Mohamad Farid, Won Seog Kim, Seok Jin Kim, Seong Hyun Jeong, Jong-Ho Won, Nooraisyah Ismail, Soon Thye Lim
Journal: Blood (2014)
Abstract 2994: Clinical applications of comprehensive genome analysis of papillary renal cell carcinoma, type II
Authors: Ji-Yeon Kim, Se-Hoon Lee, Soojin Cha, Kyung Chul Moon, Jong-Il Kim, Dae Seog Heo
Journal: Cancer Research (2015)

Abstract Purpose Papillary renal cell carcinoma (PRCC) is the most common type of non-clear cell renal cell carcinoma (NCCRCC). Of PRCC, PRCC,type2(PRCC2) is known to have highly aggressiveness and relative drug resistance. In contrast of clear cell renal cell carcinoma (CCRCC), we poorly understand genetic alterations to drive PRCC2. Moreover, though many tyrosine kinase inhibitors (TKIs) are now available to treat PRCC, the predictive marker of TKIs is not in existence. Therefore, we aimed to analyze genetic alteration of PRCC2. Patients and Methods We performed whole-exome sequencing (WES) of DNA from 9 PRCC2 samples and matched normal tissue. In addition, whole-transcriptome sequencing (WTS) was conducted for 7 of these samples. We analyzed somatic mutations, copy number alterations, germ line mutations using WES data, pathway alterations and gene fusions through RNA expression data. We investigated the relationship between clinical prognosis and genetic alterations. Results Of nine samples, average non-silent mutation rate is 1.13 mutations per Mb (range, 0.49 to 2.14 mutations per Mbs). Forty-seven somatic mutations including SRRD(four), PKD1L2(three) and MX1(three) are discovered in more than 2 specimens. The genes associated to histone modification and ubiqutination are frequently altered. We found FH somatic mutation, a potent target of VEGFR TKI, in young female PRCC2 patient. Her tumor is extremely shrunk after 6cycles treatment and after that she received pazopanib for 52weeks maintaining effective response. Conclusion We suggest the possibility of translational research from sequencing data to real medical treatment of PRCC2. This pivotal study demonstrates that novel somatic FH mutation is the therapeutic target of VEGFR TKI. Therefore, further large scaled comprehensive genetic analysis of PRCC2 is required to propose personalized medicine for conquering papillary renal cell carcinoma, type 2. Note: This abstract was not presented at the meeting. Citation Format: Ji-Yeon Kim, Se-Hoon Lee, Soojin Cha, Kyung Chul Moon, Jong-Il Kim, Dae Seog Heo. Clinical applications of comprehensive genome analysis of papillary renal cell carcinoma, type II. [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 2994. doi:10.1158/1538-7445.AM2015-2994
Referral patterns and use of fertility preservation in patients with cancer.
Authors: G. P. Quinn, C. Silva, M. C. Lee, S. T. Vadaparampil, L. Hildreth, S. Plosker
Journal: Journal of Clinical Oncology (2011)

e19535 Background: ASCO guidelines suggest oncologists discuss risk of infertility with all newly diagnosed cancer patients of childbearing age and refer interested patients to a reproductive endocrinologist (REI). An NCI cancer center developed a referral system to increase patient awareness and decrease physician burden. This study examined uptake patterns of referrals to a REI. Methods: The patient-reported electronic questionnaire (EQ) of the cancer center asks patients to respond (yes/no/not sure) to 2 questions: Are you interested in having a child (more children) in the future? Would you like a referral to a REI to discuss your options? Responses were collected from June – Dec 2010 from patients aged 18-45. A retrospective record review was also conducted at the REI clinic where patients are referred. Gender, cancer type were extracted along with use of fertility preservation (FP) methods. Results: 922 patients age 18-45 were seen at the cancer center during this 6 month period. 161 females and 12 males indicated an interest in having more children and 102 noted “not sure”. 87 females and 11 males requested a REI referral. REI clinic records show 41 phone calls were made during this period for a consult (cancer site = breast (17%); hematologic cancer (30%). 5 males and 5 females opted to use FP. Prior to the EQ, the REI clinic received 25 calls from cancer patients in a 1 yr period. Conclusions: EQ questions increase the likelihood of interested patients receiving desired referrals to REI. Patients typically want only a phone consult and <5% of females and 10% of males utilize FP. The rate of patients choosing “not sure” indicates need for further follow up. It is likely that some patients are in distress at the time of completion of the EQ and unaware of the optimal window of time for FP procedures. Further, low uptake of FP may be related to other factors such as concerns regarding treatment delay, financial resources, or distress over cancer diagnosis.
Outcomes of HIV-positive lymphoma patients treated in the highly active antiretroviral therapy (HAART) era.
Authors: M. A. Fanale, K. Vigil, C. Lai, L. Feng, W. Dong, A. Younes, J. E. Romaguera, L. Fayad, F. B. Hagemeister, V. Mulanovich
Journal: Journal of Clinical Oncology (2011)

e18528 Background: The addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and intensification with R plus EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) have improved survival for AIDS-related non-Hodgkin lymphomas (NHL) (Bouë, F, et al, JCO, 2006 and Dunleavy, K, et al, Blood, 2010). R-HCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with R-MTX-ARA-C (methotrexate, cytarabine) is also highly effective for diffuse large B cell (DLBCL), Burkitt (BL), and Burkitt-like lymphomas (BLL) (Fayad, L, et al, ASCO, 2007 and Thomas, D, et al, Cancer, 2006). Furthermore, heightened responses are described for HIV-Hodgkin lymphoma (HL) patients treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and HAART (Xicoy, B, et al, Haematologica, 2007 and Sunil, M, et al, ASH, 2009). Methods: We conducted a retrospective study to evaluate outcomes and characteristics of HIV patients with newly diagnosed lymphoma treated at M.D. Anderson Cancer Center from 1998 to 2010. Results: 56 patients were identified, 93% were male, and all but 2 were on HAART. Median age was 42.5 and 73.2% had advanced stage disease. Diagnoses included DLBCL (36%), BL (29%), BLL (25%), T-cell lymphoma (3%), and HL (7%). 80% of the DLBCL, BL, and BLL patients received CHOP (n=11), HCVAD/MTX-ARA-C (n=17), or dose-adjusted (DA) EPOCH (n=8) with 77% incorporation of R. Complete remissions (CR) occurred in 94% of DLBCL, 77% of BL, and 69% of BLL patients. Only 1 HL patient treated with ABVD entered into CR. At a median follow-up of 21.6 months 5 patients relapsed and 19 died. Patients with a CD4 count >100 had superior progression free survival (PFS) and overall survival (OS) (p= 0.019, p=0.016). In addition, HIV diagnosis of < 6 months improved OS (p=0.012), and a non-significant improvement in PFS and OS was seen for BL and BLL patients with DA-EPOCH+/-R. Conclusions: Our data highlights that CD4 count at diagnosis and time from HIV diagnosis are important prognostic factors for patients with HIV and lymphoma. While a small group size and varied regimens are limiting factors, a trend towards decreased BL or BLL progression or relapse was seen with DA-EPOCH+/-R.