bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 949: Progesterone receptor/IRS-1 cooperation promotes stem cell outgrowth and endocrine resistance in estrogen receptor-positive luminal breast cancer
Authors: Dwyer Amy R. , Sachdev Deepali , Lange Carol A. 
Published: August 2018

Abstract
Luminal breast cancers account for ~75% of all cases and while adjuvant hormone therapy targeting ERα has significantly improved overall survival for patients with ER+ tumors, acquired resistance remains a major clinical problem. Tamoxifen-resistant (TamR) breast cancer models show loss of IGF1R concomitant with increased insulin-induced growth, underpinned by insulin receptor (InsR) compensation for IGF1R loss. PR (gene name PGR) is an estrogen-regulated target gene whose expression is used as a clinical marker of ER activity. However, its de novo relevance to breast cancer is unclear. We have shown previously that post-translational modifications create unique PR species whose altered behavior drives an endocrine-resistant gene signature, in part by crosstalk with the IGFR pathway. We propose that phospho-PR target gene selectivity is mediated by cooperation between PR-B and InsR/IGF1R pathway components. Herein we show that phospho-PR-expressing T47D cells lose expression of IGF1R compared to control cells expressing WT PR-B. Furthermore, expression of the adapter protein IRS-1 requires PRB expression and these IRS-1+ cells were more sensitive to insulin in anchorage-dependent growth assays. Phospho-PR T47D cells exhibit increased ALDH+ and CD24-/CD44+ tumorsphere formation compared to wt PRB-expressing cells. Inhibitors targeting IRS-1 and InsR were used to test their requirement for tumorsphere growth and, surprisingly, IRS-1 perturbation reduced phospho-PRB but not wt PRB tumorsphere growth. Interestingly, IRS-1 replaces IGF1R in phospho-PRB-containing transcriptional complexes that are recruited to the CTSD promoter, which we previously identified as a phospho-PR target gene. Finally, breast cancer cells expressing phospho-PR species exhibited tamoxifen-resistant growth. Collectively our data suggest that phospho-PRB cooperates with IRS-1 downstream of the Ins/IGF1R system to promote outgrowth of endocrine-resistant cells that include ALDH+ stem-like cells capable of forming secondary tumorspheres in vitro. Targeting phospho-PR species in addition to the signaling components of PR-complexes may provide a means to block emergence of endocrine-resistant cancer cells during breast cancer progression.
Citation Format: Amy R. Dwyer, Deepali Sachdev, Carol A. Lange. Progesterone receptor/IRS-1 cooperation promotes stem cell outgrowth and endocrine resistance in estrogen receptor-positive luminal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 949.
Abstract 962: Testing T cell co-potentiation as an antitumor therapeutic strategy in humanized mouse models
Authors: Nelson Alfreda D. , Elsbernd Laura , Schrum Adam G. , Pages Diana Gil 
Published: August 2018

Abstract
We recently described the concept of T cell co-potentiation as means to target antigen recognition by T cells to achieve antitumor immunotherapy in mouse models. Normally, T cell antigen receptor (TCR) engagement by a strong immunogenic antigen induces a CD3 conformational change that exposes a proline-rich sequence (PRS) in the cytosolic domain of CD3 epsilon (CD3e) to dock cytosolic proteins and contribute to the assembly of the signaling cascade that activates T cell immune function. While induction of CD3 conformational change is required by T cells to achieve productive TCR/CD3 signaling, this molecular event fails to occur when the TCR interacts with poorly immunogenic antigens, like most tumor-associated antigens (TAAs). We found that CD3 conformational change can be exogenously induced on T cells using monovalent Fab fragments (Mono-Fabs) specific for the CD3 complex. Anti-CD3 Mono-Fabs expose the CD3e PRS, but fail to crosslink the TCR/CD3, turning them incompetent to trigger T cell activation in the absence of additional stimulation. However, if TCR has bound a weak antigen, one that fails to induce CD3 conformational change intrinsically, then anti-CD3 Mono-Fabs enable TCR/CD3 signaling, and as a result co-potentiate T cell responses to weak antigenic stimulation. Using a mouse model for melanoma (B6 mice and B16-F10 melanoma cell line), we found that treatment of mice with anti-CD3e Mono-Fabs improved antitumor T cell responses against melanoma in an antigen-dependent manner, and dramatically improved the outcome of complementary T cell immunotherapies. Based on these observations, we hypothesize that T cell co-potentiation using anti-human CD3 Mono-Fabs can be exploited as a novel immunotherapy for cancer patients. We have recently identified one anti-human CD3 Mono-Fab that is capable to induce CD3 conformational change in human T cells and allows the co-potentiation of T cell response to weak antigenic stimulation. Here we present data from human T cells and humanized mouse models using this Mono-Fab that support the potential therapeutic value of exploiting T cell co-potentiation to treat cancer patients.
Citation Format: Alfreda D. Nelson, Laura Elsbernd, Adam G. Schrum, Diana Gil Pages. Testing T cell co-potentiation as an antitumor therapeutic strategy in humanized mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 962.
Abstract 989: Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages and can form chimeric mammary glands in vivo
Authors: Rosenbluth Jennifer M. , Schackmann Ronald , Li Carman , Sachs Norman , Dillon Deborah , Richardson Andrea , Brock Jane , Garber Judy , Gray Gary Kenneth , Zoeller Jason , Boedicker Mackenzie , Kuiken Hendrick Johannes , Clevers Hans , Brugge Joan 
Published: August 2018

Abstract
Use of cell culture models to investigate the development of cancer associated with familial breast cancer syndromes is challenging because many culture methodologies do not maintain all of the lineages that are present in vivo, particularly the progenitor cells that may be the specific cancer cell-of-origin. We evaluated the ability of organoid culture technology to preserve stem/progenitor and differentiated cell types via long-term propagation of normal human mammary tissues. Tissue samples were obtained from elective reduction mammoplasties or from prophylactic mastectomies for cancer prevention, and were histologically normal. These were grown using conditions similar to organoid cultures for other epithelial cell types, as has been recently described (Sachs et al., Cell 2018). We found that basal stem and luminal progenitor cells could be cultured long-term, and differentiated in culture to generate mature basal and luminal cell types. Analysis of matched organoid cultures and native tissues by mass cytometry (CyTOF) for 38 markers at single-cell resolution confirmed the presence of multiple mammary epithelial cell types in the organoids, and demonstrated that protein expression patterns of the tissue of origin were largely preserved in culture. In addition, we generated a panel of over 40 mammary organoids derived from patients harboring inherited mutations in the cancer predisposition gene BRCA1 and from unaffected controls. Despite interindividual variability, an expansion in luminal progenitor populations associated with BRCA1 mutation could be detected in cultured organoids. Human mammary organoids heterozygous for BRCA1 could be engrafted into the murine mammary gland, resulting in mixed ductal and acinar structures. These studies indicate that this new model system is well suited for studies of aberrant phenotypes associated with BRCA1 mutation and approaches to prevent cancer development in these genetically predisposed tissues.
Citation Format: Jennifer M. Rosenbluth, Ronald Schackmann, Carman Li, Norman Sachs, Deborah Dillon, Andrea Richardson, Jane Brock, Judy Garber, Gary Kenneth Gray, Jason Zoeller, Mackenzie Boedicker, Hendrick Johannes Kuiken, Hans Clevers, Joan Brugge. Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages and can form chimeric mammary glands in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 989.
Abstract CT061: Interim results of a phase Ia clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients
Authors: Head Jonathan F. , Daniels Gregory A. , McKinney Michelle A. , Ongkeko Weg M. , Sakamoto Kyoko , Wang-Rodriguez Jessica 
Published: August 2018

Abstract
While progress has occurred in both cellular and immune checkpoint therapy, the benefit of therapeutic cancer vaccines has been difficult to demonstrate. Prostate cancer may be an exception with the modest activity of sipuleucel-T. We have developed a potentially lower cost and easy to administer therapeutic vaccine with the combination of tumor antigen (PSA) and biologic adjuvants (IL-2 and GM-CSF). This study is a Phase 1a clinical trial of a PSA/IL-2/GM-CSF vaccine in 20 biochemically recurrent hormone-naïve and hormone-independent prostate cancer patients. Major inclusion criteria include adenocarcinoma of the prostate, rising serum PSA and no measurable disease. Phase 1a examines the rate of serious adverse events (SAEs) and dose limiting adverse events (DLAEs) in an initial course of 6 vaccinations (“induction vaccination”). Twenty patients enrolled and nineteen patients completed all six intradermal injections (one patient received 5 vaccines, missed week 11 vaccine) of the PSA/IL-2/GM-CSF vaccine at weeks 1, 2, 3, 7, 11 and 15. None of the patients vaccinated in the Phase 1a portion had a SAE or DLAE with the most common AE relating to grade 1 injection site reactions. Fifteen of the 18 patients who received vaccines had immune responses to PSA as demonstrated in a lymphocyte blastogenesis assay by week 31. Interestingly, after vaccination 14 of 20 patients had an increase in the doubling time of their serum PSA, suggesting a slowing of the growth of the prostate cancer. Four of 20 patients have progressed (3 PSA progression and 1 radiological progression) at 31 weeks follow-up.
Citation Format: Jonathan F. Head, Gregory A. Daniels, Michelle A. McKinney, Weg M. Ongkeko, Kyoko Sakamoto, Jessica Wang-Rodriguez. Interim results of a phase Ia clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT061.
Abstract CT082: TTFields concurrent with standard of care for the treatment of stage 4 non-small cell lung cancer (NSCLC) following platinum failure: phase III LUNAR study
Authors: Weinberg Uri , Farber Ori , Giladi Moshe , Bomzon Zeev , Kirson Eilon 
Published: August 2018

Abstract
Tumor Treating Fields (TTFields) are a non-invasive, anti-mitotic treatment modality. TTFields disrupt the formation of the mitotic spindle, and dislocation of intracellular constituents. TTFields significantly extend the survival of newly diagnosed glioblastoma patients when combined with temozolomide. Efficacy of TTFields in NSCLC has been shown preclinically and their safety in a phase I/II pilot study with pemetrexed. We hypothesize that adding TTFields to immune checkpoint inhibitor or docetaxel following platinum doublet failure will increase OS.
Methods: Patients (N=534) with squamous or non-squamous NSCLC are enrolled in the LUNAR phase III study [NCT02973789]. Patients are stratified by their selected standard therapy (immune checkpoint inhibitors or docetaxel), histology (squamous vs. non-squamous) and geographical region. Key inclusion criteria are disease progression while on or after platinum-based systemic therapy, ECOG 0-2, no electronic medical devices in the upper torso, and absence of brain metastasis. Docetaxel or immune checkpoint inhibitors are given at standard doses. TTFields are applied to the upper torso for 18 hours/day, allowing patients to maintain daily activities. TTFields are continued until progression in the thorax and/or liver. Follow up is performed every 6 weeks, including CT scans of the chest and abdomen. On progression in the thorax and/or liver, patients have three post-progression follow up visits and are later followed monthly for survival. The primary endpoint is superiority in OS between patients treated with TTFields in combination with the standard of care treatments, compared to standard of care treatments alone. Key secondary endpoints compare the OS in patients treated with TTFields and docetaxel Vs. those treated with docetaxel alone, and patients treated with TTFields and immune checkpoint inhibitors Vs. those treated with immune checkpoint inhibitors alone. An exploratory analysis will test non-inferiority of TTFields with docetaxel compared to checkpoint inhibitors alone. Secondary endpoints include progression-free survival, radiological response rate, quality of life based on the EORTC QLQ C30 questionnaire and severity & frequency of adverse events. The sample size is powered to detect a HR of 0.75 in TTFields-treated patients versus control group.
Citation Format: Uri Weinberg, Ori Farber, Moshe Giladi, Zeev Bomzon, Eilon Kirson. TTFields concurrent with standard of care for the treatment of stage 4 non-small cell lung cancer (NSCLC) following platinum failure: phase III LUNAR study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT082.
Abstract CT085: Randomized phase II trial of hydroxychloroquine in combination with gemcitabine/nab-paclitaxel to inhibit autophagy in pancreatic cancer: A SU2C-funded trial
Authors: Karasic Thomas B. , O'Hara Mark H. , Loaiza-Bonilla Arturo , Reiss-Binder Kim A. , Teitelbaum Ursina R. , Borazanci Erkut , Jesus-Acosta Ana M. De , Redlinger Colleen , Burrell Jessica A. , Hoff Daniel D. Von , Laheru Daniel A. , Amaravadi Ravi K. , Drebin Jeffrey A. , O'Dwyer Peter J. 
Published: August 2018

Abstract
Autophagy, a regulated metabolic process that enables energy conservation in adverse environmental circumstances, has been shown in animal models to confer resistance to chemotherapy, which can be reversed by hydroxychloroquine (HCQ). After establishing safety in a Phase I run-in, 112 patients were randomized to receive standard gemcitabine (1000mg/m2) and nab-paclitaxel (125 mg/m2) weekly x 3 every 4 weeks, with (n=55 evaluable) or without (n=55 evaluable) HCQ 600mg bid. Median age was 65 (range 43-86) of whom 47% were aged &gt; 65, 40% were female, 93% Caucasian, ECOG PS 0/1 51%/49%, and did not differ between the arms. Treatment-related side-effects were consistent with prior studies, and were balanced by arm, except for Grade 3/4 neutropenia (42 vs 23%), nausea (9 vs 0%), and fatigue (7 vs 0%), all higher with HCQ. Partial responses were observed in 21/46 (46%) with HCQ, and 8/48 (17%) without HCQ. The primary endpoint, overall survival at 12 months, was 41% (95% CI 27-53%) in the HCQ arm and 51% (95% CI 36-63%) in the non-HCQ arm. Median progression-free survival was 5.7 months (95% CI 4.0-9.3) in the HCQ arm and 6.4 months in the non-HCQ arm (95% CI 4.5-7.6). Median overall survival was 11.1 months (95% CI 9.0-14.2) in the HCQ arm and 14.4 months (95% CI 9.5-15.6) in the non-HCQ arm. Genomic testing was performed on a subset of the patients (41%), in whom outcomes did not differ by p53 mutational status. We conclude that based on the primary endpoint, the addition of the autophagy reversal agent HCQ did not improve the survival of patients with metastatic pancreatic cancer. Response rates in patients who received HCQ were higher, and toxicity was tolerable. Autophagy reversal might be explored in the management of locally-advanced disease.
Citation Format: Thomas B. Karasic, Mark H. O'Hara, Arturo Loaiza-Bonilla, Kim A. Reiss-Binder, Ursina R. Teitelbaum, Erkut Borazanci, Ana M. De Jesus-Acosta, Colleen Redlinger, Jessica A. Burrell, Daniel D. Von Hoff, Daniel A. Laheru, Ravi K. Amaravadi, Jeffrey A. Drebin, Peter J. O'Dwyer. Randomized phase II trial of hydroxychloroquine in combination with gemcitabine/nab-paclitaxel to inhibit autophagy in pancreatic cancer: A SU2C-funded trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT085.
Abstract CT089: The Dutch Oncology Research Platform (DORP), a national infrastructure for investigator-initiated multicenter clinical cancer research
Authors: Punt Cornelis J. 
Published: August 2018

Abstract
Background Investigator-initiated clinical cancer research (IICCR) contributes in a major way to improved prognosis of cancer patients. However, increased complexity of legislation and regulation, lack of uniformity in local procedures among participating hospitals, and increasing demands on monitoring seriously endanger IICCR, since insufficient staff/funding is available to meet these requirements. In addition, better characterization of patient subgroups requiring specific treatments hamper the feasibility of randomized studies with classic design, and calls for innovative study designs. In The Netherlands, tumor-specific research groups exist for almost every tumor type, which however have different levels of professionalization, but which all face the same problems. This seriously hampers future development of IICCR.
Methods A national infrastructure (DORP) has been developed to facilitate IICCR. DORP has 3 pillars: statistical support, monitoring, and project management. DORP provides statistical and logistic support in protocol development according to up-to-date standards, and, once financial support for the conduct of the study (i.e. datamanagement) has been obtained, provides support for monitoring and project management. The latter includes implementation of the study in participating hospitals, and administrative/financial management of the study. DORP statisticians will develop innovative trial designs that provide more feasible alternatives to classic phase 3 studies in small subgroups of patients, and DORP project managers will aim to harmonize local study procedures in hospitals in order to speed up study initiation.
Results The DORP initiative has been received with great enthousiasm among stakeholders (i.e. research groups, patient advocacy groups, large trial offices, professional and hospital organisations, insurance companies). DORP has recently received a 6.5 million euro starting grant from the Dutch Cancer Society (KWF Kankerbestrijding), which has allowed to established DORP as a cooperation in which all stakeholders participate. A total of approx. 30 statisticians, monitors and project managers will be recruited and will be employed at institutions with established expertise in the respective fields. A director has been commissioned by the board. Trial development with DORP support has been initiated in January 2018.
Conclusion The objective of DORP is more trials, for more patients, of better quality, that are timely completed. DORP may internationally provide an example for IICCR support.
Citation Format: Cornelis J. Punt. The Dutch Oncology Research Platform (DORP), a national infrastructure for investigator-initiated multicenter clinical cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT089.
Abstract CT139: Durability of responses to the combination of SD-101 and pembrolizumab in advanced metastatic melanoma: Results of a phase Ib, multicenter study
Authors: Ribas Antoni , Medina Theresa , Kummar Shivaani , Amin Asim , Drabick Joseph J. , Barve Minal , Daniels Gregory , Wong Deborah L. , Schmidt Emmett V. , Leung Abraham C. , Janssen Robert 
Published: August 2018

Abstract
Background: This phase 1b trial evaluates the safety and antitumor efficacy of the combination of SD-101, a synthetic CpG-oligonucleotide that stimulates Toll-like receptor 9 (TLR9), and pembrolizumab in patients with recurrent Stage IIIC/IV malignant melanoma.
Methods: Dose escalation of SD-101 used a modified 3+3 design. SD-101 was injected in a single tumor lesion (weekly x 4 doses then every 3 weeks x 7 doses over 6 months) at 1, 2, 4, or 8 mg and pembrolizumab was administered intravenously at 200 mg every 3 weeks up to 2 years. Tumor responses were assessed per investigator using RECIST v1.1 taking into account both injected and non-injected lesions.
Results: Of the 22 patients, 9 were naïve to anti-PD-1/L1 therapy at baseline and 13 had progressive disease while receiving prior anti-PD-1/L1 therapy. Treatment was well tolerated with no Grade 3 or higher treatment-related AEs in longer term follow up. Among the 9 patients who were anti-PD-1/L1 naïve, best objective responses were CR: 2, PR: 5, PD: 1, not evaluated [NE]: 1. Median PFS, duration of response, and OS have not been reached. Estimated 12 month PFS was 88% and OS was 89%. After a median of 18 months of follow-up, 86% of responses were ongoing. One patient with a PR developed progressive disease after 20 months of treatment. Among patients who had received prior anti-PD-1/L1 therapy, best objective responses were PR: 2, SD: 5, PD: 5, NE: 1. One patient with stable disease and 1 patient with a PR continued on combination therapy without progression for at least 10.5 months. The other 10 patients developed progressive disease ranging from 1.5 to 8 months after enrollment. Percent change in tumor size from baseline in injected and non-injected lesions will also be presented.
Conclusion: These early results suggest that combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially provide more clinical responses that are meaningfully durable than PD-1 blockade alone based on historical data.
Citation Format: Antoni Ribas, Theresa Medina, Shivaani Kummar, Asim Amin, Joseph J. Drabick, Minal Barve, Gregory Daniels, Deborah L. Wong, Emmett V. Schmidt, Abraham C. Leung, Robert Janssen. Durability of responses to the combination of SD-101 and pembrolizumab in advanced metastatic melanoma: Results of a phase Ib, multicenter study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT139.