bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 43: Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer
Authors: Snyder Lawrence B. , Neklesa Taavi K. , Chen Xin , Dong Hanqing , Ferraro Caterina , Gordon Deborah A. , Macaluso Jennifer , Pizzano Jennifer , Wang Jing , Willard Ryan R. , Vitale Nicholas , Peck Ron , Moore Marcia Dougan , Crews Craig M. , Houston John , Crew Andrew P. , Taylor Ian
Published: July 2021

Prostate cancer is the second leading cause of cancer death in men in the United States. The androgen receptor (AR) plays critical roles in both early disease and advanced prostate cancer. Current therapeutic approaches targeting the androgen/AR axis are initially effective, but castration resistant prostate cancer (CRPC) inevitably develops. CRPC is tightly linked with increased AR activity via gene overexpression, amplification, and gain-of-function mutations. To address these mechanisms of AR-dependent prostate tumor growth, we have developed a novel therapeutic agent, ARV-110, a proteolysis targeting chimera (PROTAC®) that induces a protein-protein interaction between the AR and E3 ubiquitin ligase complexes, leading to the ubiquitination of AR and its subsequent degradation via the proteasome. In vitro, ARV-110 robustly degrades AR in various prostate cancer cell lines with a half-maximal degradation concentration (DC50) of ~1 nM. Whole cell lysate proteomics and ubiquitin proteomics demonstrated high selectivity for AR in VCaP cells. ARV-110 potently downregulates androgen responsive genes, inhibits proliferation and induces apoptosis in AR dependent prostate cancer cells. In vivo, ARV-110 is orally bioavailable and robustly degrades AR with a >90% observed maximum degradation (Dmax) at efficacious doses. ARV-110 significantly and dose-dependently inhibits tumor growth in murine LNCaP and VCaP xenograft models, including enzalutamide-resistant VCaP and enzalutamide-insensitive patient-derived xenograft models. These preclinical data supported the clinical development of ARV-110 for the treatment of men with metastatic CRPC. The discovery, chemical structure and initial clinical data of ARV-110 will be presented

Citation Format: Lawrence B. Snyder, Taavi K. Neklesa, Xin Chen, Hanqing Dong, Caterina Ferraro, Deborah A. Gordon, Jennifer Macaluso, Jennifer Pizzano, Jing Wang, Ryan R. Willard, Nicholas Vitale, Ron Peck, Marcia Dougan Moore, Craig M. Crews, John Houston, Andrew P. Crew, Ian Taylor. Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 43.
Abstract 482: Rapid highly multiplexed immunoprofiling of human fixed tissues by Orion imaging
Authors: Lin Jia-Ren , Campton Daniel E. , Cooper Jeremy , Chen Yu-An , McCarty Erin F. , Ligon Keith L. , Kaldjian Eric P. , Teplitz Kyla , Reese Steve , Santagata Sandro , Sorger Peter K.
Published: July 2021

The dramatic impact of immune checkpoint inhibitors (ICIs) has focused interest in investigating immune-tumor cell interactions to understand mechanisms of ICI sensitivity and resistance, to identify patients that are responsive to specific treatments, and to develop new therapies. Multiplexed tissue imaging is a highly promising approach to immunoprofile tumors; it can assess many cell types and states within the context of preserved tumor architecture. However, the promise of highly multiplexed tissue imaging remains largely unfulfilled by current methods which are not compatible with pathology workflows. Here we present the development and implementation of Orion™ technology that permits whole-slide rapid single-pass imaging of up to 21 markers from formalin fixed paraffin embedded (FFPE) tissues. This method measures spectra for specific fluorophores to optimally sample the emitted light spectrum and distinguish multiple fluorescence excitation and emission channels across the spectral range of optical microscopes (~400-900 nm). To establish the utility of the Orion™ platform for immuno-phenotyping and immune checkpoint protein detection, we created an immunoprofiling panel of 21 qualified antibodies and labelled with fluorophores to subdivide the available emission spectrum in the 438-893 nm range. The panel includes markers that define subsets of T cells and macrophages. FFPE sections of human tonsil and matched primary and brain metastatic lung adenocarcinoma were stained and imaged in a single pass demonstrating staining patterns consistent with known micro-anatomic compartments and cell types in tonsil and identifying immune cell subtypes and heterogeneous checkpoint protein expression in tumor samples. An unexpected benefit of imaging with the Orion platform is the reduction of autofluorescence which is highly advantageous for the detection of proteins, like PD-L1, that function at very low levels. Orion imaging promises to accelerate discovery of predictive and prognostic biomarkers, enable pharmacodynamics study of immuno-oncology drugs undergoing clinical trials and ultimately provide clinically actionable diagnostic tests.

Citation Format: Jia-Ren Lin, Daniel E. Campton, Jeremy Cooper, Yu-An Chen, Erin F. McCarty, Keith L. Ligon, Eric P. Kaldjian, Kyla Teplitz, Steve Reese, Sandro Santagata, Peter K. Sorger. Rapid highly multiplexed immunoprofiling of human fixed tissues by Orion imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 482.
Abstract 520: Potential role of serum proteome in predicting immune-related adverse events from immunotherapy in non-small cell lung cancer
Authors: Nam Myungwoo , Kim Leeseul , Cheng William , Bae William H. , Hwang Jin Young , Choi Yoonhee , Lee Yeun Ho , Hur Won Kyung , Jung Chan Mi , Cho Heayoon S. , Chae Young Kwang
Published: July 2021

Early recognition of immune-related adverse events (irAEs) of immunotherapy is important. Circulating proteome reflects host response to diseases and is being explored as a marker for response to immunotherapy. We used a serum-based proteomics test, Primary Immune Response (PIR), to explore the associations between developing irAEs and immunotherapy in non-small cell lung cancer (NSCLC) patients.

Data of 38 consented NSCLC patients with baseline PIR test done within one week prior to the start of immunotherapy were collected. Samples were grouped into either sensitive or intermediate/resistant (not sensitive) by PIR classification. We analyzed the durations from the immunotherapy initiation to the first episode of irAE, each individual irAE, and each irAE above grade 1 using log-rank test. IrAEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Among the 38 NSCLC patients, 21 patients (55%) experienced one or more irAEs. The total number of irAEs was 33 with the majority classified as either grade 1 (n=18, 55%) or grade 2 (n=11, 33%) (Table 1). PIR-sensitive group showed longer irAE free period with the median ‘Time to first irAE' being 54 weeks compared to 9.5 weeks in PIR-not sensitive (p=0.22, HR=0.56, 95% CI=0.24-1.34). The median ‘Time to each irAE' were 45 weeks and 12 weeks in PIR-sensitive and PIR-not sensitive, respectively (p=0.1, HR=0.55, 95% CI=0.28-1.1). The median ‘Time to each irAE above grade 1' demonstrated similar results with less differences between the two groups with median values of 54 weeks and 30 weeks in PIR-sensitive and PIR-not sensitive, respectively (p=0.28, HR=0.57, 95% CI=0.21-1.56).

Our results demonstrated a trend that PIR-sensitive patients are more likely to tolerate immunotherapy longer without developing irAEs. It implies the potential value of the baseline PIR test in predicting the development of irAEs and selecting subsets of patients who need close monitoring with immunotherapy.

Distribution of irAEs by PIR classificationVariablesSensitiveNot-sensitiveTotal number of patients, n1325Patients without irAE, n (%)7 (54%)10 (40%)Patients with irAE, n (%)6 (46%)15 (60%)Total number of irAEs, n1023Grade 1, n (%)5 (50%)13 (57%)Grade 2, n (%)5 (50%)6 (26%)Grade 3, n (%)02 (8%)Grade 4, n (%)01 (4%)Grade 5, n (%)01 (4%)

Citation Format: Myungwoo Nam, Leeseul Kim, William Cheng, William H. Bae, Jin Young Hwang, Yoonhee Choi, Yeun Ho Lee, Won Kyung Hur, Chan Mi Jung, Heayoon S. Cho, Young Kwang Chae. Potential role of serum proteome in predicting immune-related adverse events from immunotherapy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 520.
Abstract 626: The neoantigen and immune landscape of epithelial mesenchymal transition (EMT) low and high score serous ovarian cancers
Authors: Hur Won Kyung , Hwang Jin Young , Kim Leeseul , Nam Myungwoo , Bae William H. , Choi Yoonhee , Lee Yeun Ho , Cho Heayoon S. , Yu Emma , Jung Chan Mi , Cheng William , Kim Eugene , Low Christmann , Wang Victor , Chuang Jeff , Chae Young Kwang
Published: July 2021

Background: Apart from its role in ovarian cancer progression, epithelial-mesenchymal transition (EMT) can promote chemotherapy resistance. We aimed to analyze how the EMT score would affect the tumor microenvironment in ovarian cancer.

Methods: cBioportal was queried to obtain The Cancer Genome Atlas (TCGA) data for the serous ovarian cancer (SOC) cohort (TCGA, 585 patients). The neoantigen prediction data was derived from the CloudNeo pipeline using TCGA mutation calling. EMT scores were calculated by subtracting the average RNA-seq z-scores of three epithelial marker genes from the average RNA-seq z-scores of 13 mesenchymal marker genes as described in the previous study. Patient samples were grouped as either EMT-high (highest 1/3) or EMT-low (lowest 1/3). CIBERSORT was applied to predict the tumor-infiltrating immune cells.

Results: Among the 585 SOC patients, only 256 patients had mutation data available for our analysis. The EMT-low group had a significantly higher mutation count (p value=0.0004) and cytolytic score (p value=0.032) than the EMT-high group. In addition, the EMT-low samples were associated with improved overall survival in SOC patients (HR, 0.55; 95% CI, 0.39-0.78; P < 0.001). The median survival of EMT-low was 57.40, and EMT-high was 41.06 months. Neoantigen counts and PD-L1 express level tended to be higher in the EMT-high group although failed to show statistical significance. The immune cell infiltration rates were not different between both groups.

Conclusions: Our study is the first to describe the association between the EMT potential, neoantigen counts, and cytolytic scores in SOC. In our analyses, tumors with low EMT potential had a significantly higher neoantigen burden and higher cytolytic scores, suggesting that tumors with low EMT potentials tend to be more immunogenic. Further studies are warranted to explore the utility of EMT scores as biomarkers to predict the treatment response to immunotherapy in SOC.

The immunologic characteristics of EMT low and high SOCNumber of patientsNeoantigen countp-valueMutation countp-valueCytolytic scorep-valuePD-L1 expressionp-valueEMT low6088.190.183783.190.0004183.40.032190.0663EMT high5867.7472.7486.3515.52

Citation Format: Won Kyung Hur, Jin Young Hwang, Leeseul Kim, Myungwoo Nam, William H. Bae, Yoonhee Choi, Yeun Ho Lee, Heayoon S. Cho, Emma Yu, Chan Mi Jung, William Cheng, Eugene Kim, Christmann Low, Victor Wang, Jeff Chuang, Young Kwang Chae. The neoantigen and immune landscape of epithelial mesenchymal transition (EMT) low and high score serous ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 626.
Abstract 735: hPG80 (circulating progastrin), a novel blood-based biomarker for detection of poorly differentiated neuroendocrine carcinoma and well differentiated neuroendocrine tumors
Authors: Chauhan Aman , Prieur Alexandre , Kolesar Jill , Arnold Susanne , Cousin Thierry , Payen Lea , Mahi Younes , Sanders Madison , Evers B. Mark , Joubert Dominique , Anthony Lowell
Published: July 2021

Background: Current blood-based biomarkers for neuroendocrine neoplasms (NENs) lack both sensitivity and specificity. This is especially true for high-grade NENs (small and large cell neuroendocrine carcinomas). Human circulating progastrin (hPG80) is a novel biomarker for NENs and is easily measured in plasma using an ELISA test. This study is the first to explore hPG80 in NENs.

Methods: Progastrin concentrations were quantified in plasma from 95 patients with stage IV NEN using DxPG80 technology (ECS Progastrin, Switzerland) and compared with hPG80 concentrations in 50-80-year-old healthy donors (n=252) as well as a subgroup comprised of only the 18-25-year-olds (n=137).

Results: The median hPG80 in NENs patients was 5.54 pM as compared to 1.5 pM for patients in the 50-80-year-old control group and 0.29 pM for patients in the 18-25-year-old cohort (p<0.0001, one-tailed Mann-Whitney U-test). A subgroup analysis of NENs revealed a median hPG80 of 3.54 pM in neuroendocrine carcinoma (NEC n=25) vs 5.8 pM in neuroendocrine tumor (NET n=70). Interestingly small cell lung cancer sub cohort (n=13) also showed significant elevation of hPG80 (9.09 pM). All the above-mentioned differences were statistically significant as compared to healthy controls.

Conclusions: Plasma hPG80 in NENs suggests hPG80 may be a diagnostic blood biomarker for both low- and high-grade NENs and further study is warranted. A prospective trial is ongoing in small cell lung cancer to evaluate its role in monitoring of disease (NCT03958045) and further prospective studies in low-grade neuroendocrine tumors are underway.

Citation Format: Aman Chauhan, Alexandre Prieur, Jill Kolesar, Susanne Arnold, Thierry Cousin, Lea Payen, Younes Mahi, Madison Sanders, B. Mark Evers, Dominique Joubert, Lowell Anthony. hPG80 (circulating progastrin), a novel blood-based biomarker for detection of poorly differentiated neuroendocrine carcinoma and well differentiated neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 735.
Abstract 932: Discovery of D-1553, a novel and selective KRas-G12C Inhibitor with potent anti-tumor activity in a broad spectrum of tumor cell lines and xenograft models
Authors: Shi Zhe , Weng Jifang , Fan Xiaochong , Wang Emma , Zhu Qingqing , Tao Liangshan , Han Zixing , Wang Zhenwu , Niu Haotao , Jiang Yueheng , Zhang Ling , Dai Xing , Wang Yaolin
Published: July 2021

KRas mutations are frequently seen in solid tumors such as lung (~25%), colorectal (~40%) and pancreatic (~90%) cancers. The G12C mutation accounts for ~50% of all KRas mutations in lung cancer and to a lower percentage in other tumor types. Recently, selective inhibitors targeting the KRas-G12C mutation through covalent link to the cysteine of the mutated protein have been advanced to early clinical development and exhibited encouraging response in patients with lung cancer. Here, we present a novel small molecule compound that specifically inhibits KRas-G12C in vitro (cell lines) and in vivo (cell line-derived xenograft tumor models). The anti-tumor activity of D-1553 is evaluated across a panel of cancer cell lines including lung, pancreatic and colorectal cancers and shown to be active only in cancer cells with KRas-G12C mutation. In addition, D-1553 is highly potent in vivo in various cell line-derived xenograft tumor models with KRas-G12C mutation as a single agent. When D-1553 is combined with MEK inhibitor, SHP2 inhibitor or cytotoxic agents, further tumor growth inhibition or regression was observed in tumor xenograft models. These data suggest that D-1553 has anti-tumor activity in a broad spectrum of cancers and is suitable for tissue-agnostic clinical development targeting cancers with KRas-G12C mutation. D-1553 is currently in a Phase 1/2 clinical trial evaluating safety, tolerability, PK and efficacy in patients with advanced solid tumors harboring KRasG12C mutation (NCT04585035).

Citation Format: Zhe Shi, Jifang Weng, Xiaochong Fan, Emma Wang, Qingqing Zhu, Liangshan Tao, Zixing Han, Zhenwu Wang, Haotao Niu, Yueheng Jiang, Ling Zhang, Xing Dai, Yaolin Wang. Discovery of D-1553, a novel and selective KRas-G12C Inhibitor with potent anti-tumor activity in a broad spectrum of tumor cell lines and xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 932.
Abstract 978: Magnolol induces apoptosis and inhibits metastasis via suppression of NF-κB activation in human bladder cancer
Authors: Lee Sin-Rong , Tan Zhao-Lin , Chang Yuan , Chiang I-Tsang , Hsu Fei-Ting
Published: July 2021

Magnolol is a phenolic compound extracted from magnolia officinalis, and known as a common Chinese medicinal material used in the treatment of strokes, colds, etc. Magnolol has also recognized as an anti-inflammation agent which can downregulate several inflammation signals transduction. Several reports suggested that magnolol may also have anti-tumor potential in liver and colon cancer. Nevertheless, the regulatory mechanism of magnolol on apoptosis and NF-κB signaling in human bladder cancer has not been elucidated. Thus, the purpose of the study was to investigate the mechanism and therapeutic efficacy on bladder cancer. First of all, we used MTT assay to investigate the cytotoxicity induction after magnolol treatment in bladder cancer. Then, we used NF-κB translocation assay to evaluate whether the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was decreased after magnolol treatment. We also detected the apoptosis induction ability of magnolol on extrinsic/intrinsic apoptosis pathway. This study demonstrated that magnolol significantly triggered the accumulation at the sub-G1 phase, the loss of mitochondrial membrane potential, and the activation of cleaved caspase-3, -8 and -9. Further verify the effect of magnolol on the expression of anti-apoptotic related proteins, we performed Western blotting. Magnolol inhibited migration and invasion ability of bladder cancer were investigated by wound healing and invasion assay. Then, we performed Western blotting to detect whether magnolol may inhibit NF-κB-mediated downstream signaling that involving in anti-apoptosis and metastasis such as MCL-1 and MMP9 protein expression. Moreover, the reduction of Cyclin D1 protein expression was used to evaluate the inhibition of cell proliferation by magnolol. In sum, our result demonstrated that magnolol induced extrinsic and intrinsic apoptosis mechanism and inhibit invasion/migration ability of bladder cancer was associated with the inactivation of NF-κB.

Citation Format: Sin-Rong Lee, Zhao-Lin Tan, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu. Magnolol induces apoptosis and inhibits metastasis via suppression of NF-κB activation in human bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 978.
Abstract CT153: Correlation of CDKN2A genomic alterations with tumor response to palbociclib given before chemoradiation therapy to patients with human papillomavirus-unrelated, locally advanced head and neck squamous-cell carcinoma
Authors: Oppelt Peter , Ley Jessica , Palka Kevin , Paniello Randal C. , Puram Sidharth V. , Rich Jason , Jackson Ryan , Pipkorn Patrik , Gay Hiram , Liu Jingxia , Thorstad Wade , Zevallos Jose , Adkins Douglas R.
Published: July 2021

The primary aims of this single-arm, phase 2 trial were to determine the objective response rate (ORR) of human papillomavirus (HPV)-unrelated, locally advanced head and neck squamous-cell carcinoma (LA-HNSCC) to palbociclib monotherapy, and to correlate responses to somatic genomic alterations in CDKN2A. HPV-unrelated disease was defined as 1) SCC of the larynx, hypopharynx or oral cavity, or 2) SCC of the oropharynx with <70% of tumor cells expressing p16 by immunohistochemistry and/or absence of high-risk HPV-RNA by in situ hybridization. Genome sequencing (FoundationOne CDx or Tempus xT) was performed on tumor tissue obtained before treatment. Patients received palbociclib 125 mg/d orally on days 1-21 of each 28-day cycle. Tumor response was assessed using RECIST 1.1 on CT scans performed before and after two cycles of palbociclib. After palbociclib, patients received chemoradiation therapy. A sample size of 24 patients yielded an 80% power if the ORR was >38% (alternative hypothesis), using an exact binomial test of one sample proportion comparison with an upper one-sided nominal significance level of 0.05 and null ORR of <17%. To date, 12 patients have enrolled and completed two cycles of palbociclib: primary site (larynx-7; hypopharynx-2; oropharynx-2, oral cavity-1), stage (III-3; IV-9), and smoking history (yes-11; no-1). The ORR to palbociclib monotherapy was 33%: CR (1 patient), PR (3), SD (7), and PD (1). CDKN2A alterations were identified in 6 patients (50%), and included loss-of-function mutations (4) or deletions (2). Tumor responses to palbociclib occurred in 4 of 6 patients (67%) with CDKN2A alterations versus 0 of 6 patients (0%) without CDKN2A alterations (p=0.06, Fisher's Exact Test). These preliminary results suggest that palbociclib may be an effective treatment for CDKN2A-altered, HPV-unrelated, LA-HNSCC, but not in disease that lacks CDKN2A alterations.

Citation Format: Peter Oppelt, Jessica Ley, Kevin Palka, Randal C. Paniello, Sidharth V. Puram, Jason Rich, Ryan Jackson, Patrik Pipkorn, Hiram Gay, Jingxia Liu, Wade Thorstad, Jose Zevallos, Douglas R. Adkins. Correlation of CDKN2A genomic alterations with tumor response to palbociclib given before chemoradiation therapy to patients with human papillomavirus-unrelated, locally advanced head and neck squamous-cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT153.
Abstract CT254: COMPETE Phase III Trial - Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide vs. Everolimus in Progressive GEP-NET
Authors: Wahba Mona M. , Strosberg Jonathan , Avram Anca , Aparici Carina Mari
Published: July 2021

Background Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) make up 75% of all NETs and are often diagnosed at an advanced state with only limited treatment options. Current standard therapies include somatostatin (SST) analogues and targeted drugs such as mTOR inhibitor Everolimus. While these treatments may achieve disease stabilization for a limited time, they rarely induce objective tumor remission. PRRT has recently emerged as a promising option providing more durable responses and potentially higher objective response rates. It uses radiolabeled SST analogues which specifically target and destroy tumor cells, this way significantly sparing benign tissues. PRRT with radiolabeled SST receptor (SSTR)-ligands, such as 177Lu-DOTATATE in NETTER-1, has shown promising results in the subgroup of progressive midgut NET, with significantly improved median progression-free survival (mPFS). 177Lu-Edotreotide is an innovative radiolabeled SST analogue, with a favourable safety profile and promising efficacy. Retrospective data in metastasized GEP-NET demonstrated a mPFS of 34.5 months. A prospective study of PRRT with an approved comparator has not yet been performed. Here we report the trial design and study objectives comparing the efficacy and safety of 177Lu-Edotreotide with Everolimus.

Methods Trial design COMPETE (NCT03049189) is a prospective, randomized, controlled, open-label, multi-center Phase III study to evaluate the efficacy and safety of 177Lu-Edotreotide PRRT compared to Everolimus in patients with inoperable, progressive, SSTR+ GEP-NET. 300 patients with progressive Grade 1 and 2 GEP-NET will be randomized: 200 will receive a maximum of 4 cycles of 177Lu-Edotreotide (7.5 GBq/cycle) every 3 months or until diagnosis of progression; 100 will receive 10 mg Everolimus daily for 24 months, or until diagnosis of progression. Study treatment duration/patient is 24 months.

Study Objectives Primary objective is to demonstrate prolonged mPFS in patients in the 177Lu-Edotreotide arm, vs. Everolimus.

Secondary objectives include safety, objective response rates and overall survival after treatment with 177Lu-Edotreotide, vs. Everolimus.

Conclusion COMPETE is the first pivotal study to compare PRRT in patients with Grade 1 and 2 GEP-NET using a comparator with an approved therapeutic. It is expected that COMPETE will increase their treatment options, including 1st-line therapy. Further studies with 177Lu-Edotreotide in NET patients with high unmet medical need are under review.

Citation Format: Mona M. Wahba, Jonathan Strosberg, Anca Avram, Carina Mari Aparici. COMPETE Phase III Trial - Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide vs. Everolimus in Progressive GEP-NET [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT254.
Abstract LB031: Plasma based metabolic profiling in metastatic gastrointestinal stromal tumors (GIST)
Authors: Honrao Chandrashekhar , Rao Srihari Raghavendra , Teissier Nathalie , Call S. Greg , ODay Elizabeth M. , Janku Filip
Published: July 2021

Background: Discovery of oncogenic mutations as targets for cancer therapy revolutionized treatment of GIST and other cancers. However, nearly all patients ultimately progress, which emphasizes the need for development of new tools to assess cancer prognosis and factors associated with benefit of cancer therapies. Altered metabolism is a hallmark of cancer, enabling tumors to proliferate, survive and metastasize. By measuring the complete set of metabolites in an individual (metabolome) it is possible to identify biomarkers that correlate with disease status, prognosis, and therapeutic response. Methods: We performed untargeted NMR and MS-based machine learning metabolomic analysis (Olaris, Waltham, MA) of serial plasma samples collected at baseline and during experimental systemic therapies in 39 patients with advanced/metastatic GIST. Results were compared to clinical outcomes. Results: In serial plasma samples from 39 patients with advanced/metastatic GIST using untargeted NMR and MS-based machine learning (ML) metabolomic analysis, we identified metabolic signatures to build Biomarker-of-Response (BoR) ML models that could accurately differentiate patients with response, intrinsic and adaptive resistance to experimental systemic therapies. The BoR ML model also correlated with tumor growth or tumor reduction in patients with response, intrinsic and adaptive resistance. Finally, we identified metabolic pathways associated with response and resistance. Conclusions: Comprehensive metabolomic profiling of serially collected plasma is feasible and detects metabolic signatures associated with therapeutic response in advanced GIST.

Citation Format: Chandrashekhar Honrao, Srihari Raghavendra Rao, Nathalie Teissier, S. Greg Call, Elizabeth M. ODay, Filip Janku. Plasma based metabolic profiling in metastatic gastrointestinal stromal tumors (GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB031.
Abstract LB175: APX601, a Potent TNFR2 Antagonist as a Novel and Promising Approach to Reverse Tumor Immune Suppression
Authors: Krishnan Sushma , Alvarado Ryan , Huang George , Yang Xiaodong , Filbert Erin L.
Published: July 2021

A key barrier to effective immunotherapy for cancer is the immunosuppressive tumor microenvironment (TME) characterized by infiltrating regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). While depletion of immune-suppressive cells is a promising cancer immunotherapy strategy, current approaches are ineffective due to lack of specificity and safety concerns. Tumor Necrosis Factor Receptor 2 (TNFR2) is emerging as a novel, selective target to overcome immunosuppression in the TME. Here we present APX601 as a potent Treg and myeloid suppressive cell inhibitor. APX601 is a humanized IgG1 antibody to TNFR2 generated using APXiMAB™, Apexigen's proprietary antibody platform. APX601 selectively binds human and monkey TNFR2, blocks the binding of TNFR2 to TNF-α and depletes TNFR2-expressing Treg and tumor cells in vitro. In addition to depleting suppressive cells, APX601 can also reverse MDSC and Tregs mediated immune suppression. In human TNFR2 knock-in syngeneic mouse tumor models CT26 and MC38, treatment with APX601 results in significant tumor growth inhibition both as a single agent and in combination with anti-PD-1. Thus, APX601 is a potent antagonist antibody against TNFR2 with the ability to reverse immune suppression in TME and inhibit tumor growth. APX601 was evaluated in a repeat dose range finding toxicology study in monkeys and demonstrated a good safety profile when administered up to 100mg/kg. These data strongly support the development of APX601 as a novel therapeutic approach for reversing tumor immune suppression and for the treatment solid tumors.

Citation Format: Sushma Krishnan, Ryan Alvarado, George Huang, Xiaodong Yang, Erin L. Filbert. APX601, a Potent TNFR2 Antagonist as a Novel and Promising Approach to Reverse Tumor Immune Suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB175.
Abstract LB184: Induction of ulk1 regulated autophagy by a novel antipsychotic drug leads to apoptosis in pancreatic cancer cells
Authors: Ramachandran Sharavan , Srivastava Sanjay K.
Published: July 2021

Pancreatic cancer patients have limited treatment options in spite of several advanced treatment strategies. Pancreatic tumors exhibit high basal autophagy compared to other cancers. Several studies including from our lab reported that enhanced autophagy leads to apoptosis in cancer cells. In this study, we have demonstrated that pimavanserin (PVT) suppresses pancreatic tumor growth by inducing autophagy-mediated apoptosis. Our results indicated that PVT induced 1.8 - 5 fold autophagy in pancreatic ductal adenocarcinoma (PDAC) cells, as evaluated by increased acridine orange staining. Furthermore, accumulation of double-membrane vesicles (autophagosomes) and formation of autophagolysosomes were observed with PVT treatment. Genomic analysis by R2 &GEPIA database revealed that PDAC patients exhibited reduced levels of autophagy initiator gene, ULK1. PVT induced the expression of autophagy markers ULK1, FIP200, Atg101, Beclin-1, Atg5, and LC3A/B in several pancreatic cancer cells. In addition, phosphorylation of ULK1 atSer757 was inhibited with PVT treatment. Apoptotic effects of PVT in pancreatic cancer cells were validated by increase in cleavage of caspase3. ULK1 agonist LYN-1604 enhanced the autophagic and apoptotic effects of PVT. On the other hand, autophagy inhibitors chloroquine and bafilomycin blocked the autophagic and apoptotic effects of PVT in pancreatic cancer cells. Our in vivo findings demonstrated that chloroquine abrogated the growth-suppressive effects of PVT by 21% in sub-cutaneously implanted BxPC3 tumor xenografts. Moreover, chloroquine reduced the effects of PVT in inducing the expression of ULK1 and the cleavage of caspase 3 as evaluated by western blotting. Oral administration of PVT suppressed BxPC3 tumor xenografts by 50% in athymic nude mice. In another in vivo experiment, PVT treatment inhibited the growth of orthotopically implanted PANC1 tumors by 77%. Chronic administration of PVT did not exhibit any general signs of toxicity or behavioral side effects in mice. Moreover, long-term administration of PVTdid not altered the clinical chemistry parameters like ALT, AST, total serum protein, calcium, creatinine, BUN, and albumin. Collectively, our results indicate that PVT-mediated pancreatic tumor growth suppression was associated with the induction of autophagy-mediated apoptosis. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for pancreatic cancer therapy.

Citation Format: Sharavan Ramachandran, Sanjay K. Srivastava. Induction of ulk1 regulated autophagy by a novel antipsychotic drug leads to apoptosis in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB184.
Abstract ND08: Anti-CD25 Mab: Selective depletion of T-regulatory cells
Authors: Kolben Theresa
Published: July 2021

Tregs can suppress anti-tumour immune responses allowing for tumour growth. The negative prognostic impact of Tregs has been shown in several tumor settings. So far, Treg depletion has not been successful in patients, either because relevant Treg depletion was not achieved or because Teff cells have either been impacted or depleted as well. RG6292 has been optimised for ADCC selective depletion of cells with high CD25 density (Treg) and spares effector T cells by preserving IL-2-STAT5 signaling. RG6292 is currently tested in a Ph1 dose escalation study, and is given as monotherapy i.v. Q3W in adult patients with advanced solid tumors. 29 pts have been treated thus far at dose levels ranging from 0.3 mg to 35 mg. A dose dependent peripheral Treg depletion was observed as expected from RG6292 design and a significant flux of activated CD8+T cells as well as increase of PDL1 expression and intensity were observed in 3/3 patients in on-treatment biopsies taken 28 days after initiation of treatment. RG6292 at the doses tested was well tolerated in patients with advanced metastatic solid tumors and yielded encouraging PD effects consistent with its mechanism of action.

Citation Format: Theresa Kolben. Anti-CD25 Mab: Selective depletion of T-regulatory cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND08.
Abstract ND11: The discovery and characterization of ION-537: A next generation antisense oligonucleotide inhibitor of YAP1 in preclinical cancer models
Authors: Macleod A. Robert
Published: July 2021

The tumor suppressive Hippo pathway is frequently dysregulated in cancer, resulting in the constitutive activation of YAP1 in a variety of solid cancers including hepatocellular cancer (HCC) and head and neck squamous cell carcinoma (HNSCC) among others. Here, we identified potent next-generation constrained ethyl (cEt) antisense oligonucleotides (ASOs) to selectively target either human or mouse YAP1 and evaluated these in several preclinical models of both HCC and HNSCC. In the genetically engineered mouse (GEM) model of HCC (Salvador KO mice) and in the carcinogen-induced models of HCC (diethylnitrosamine, DEN-induced HCC) systemic treatment with mouse YAP1 ASOs resulted in a marked reduction in YAP1 protein level in (~90% reduction) and strong regressions of established tumors. Interestingly, YAP1 ASO treatment also resulted in significant infiltration of T cells and myeloid lineage cells in the tumors in these immune-competent mouse models of HCC suggesting a role in immune activation. Consistent with this notion, YAP1 ASO treatment in combination with anti-PD1 antibody treatment led to enhanced antitumor activity. In HNSCC, loss of the tumor suppressor FAT1 is a frequent occurrence and results in activation and nuclear localization of YAP1. In a panel of human HNSCC cell lines, proliferation was strongly reduced by human YAP1 ASOs selectively in the cell lines harboring homozygous copy loss or nonsense mutations of FAT1 while minimal antiproliferative activity was observed in cells with wild type FAT1. Importantly, the nuclear localization of YAP1 appeared to be a key determining factor for the sensitivity of human HNSCC cells to YAP1 depletion by ASO. In vivo treatment of mice bearing human CAL33 tumors that harbor FAT1 mutation, YAP1 ASOs greatly reduced YAP1 expression in tumors and suppressed tumor growth in both subcutaneous and orthotopic models. Collectively, these results suggest a potential therapeutic use of YAP1 ASOs in the treatment of both HCC and HNSCC with YAP1 activation as a single agent or in combination with immuno-oncology drugs. Based on these finding broad human ASO clinical candidates screens were performed leading to the selection of ION-537, a potent ASO drug targeting human YAP1 has now advanced into human clinical trials in cancer patients with YAP1 activation.

Citation Format: A. Robert Macleod. The discovery and characterization of ION-537: A next generation antisense oligonucleotide inhibitor of YAP1 in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND11.
Abstract SY17-03: Tumor-associated antigen MUC1 vaccine for colon cancer prevention
Authors: Finn Olivera (Olja) J.
Published: July 2021

For most human cancers, infectious etiology is unknown and preventative vaccines based on viral antigens, such as HPV for cervical cancer, are not a possibility. However, non-viral cancer-associated antigens, self-antigens abnormally expressed on tumors, have been identified as candidates for vaccines. In patients diagnosed with cancer, preexisting immunity to some of these antigens correlates with better disease outcome or reduced risk of recurrence. In transgenic mice or other animal models where they are expressed as self-antigens, immune responses induced to their tumor forms protect from tumor challenge without causing autoimmunity. Therapeutic vaccines that have utilized these antigens have had only marginal efficacy, which extensive research has now attributed to the presence of many immunosuppressive influences in the tumor microenvironment. MUC1 is one such antigen that has been shown effective as a vaccine in preclinical animal models but has had limited immunogenicity and little efficacy as a therapeutic vaccine in numerous clinical trials in many epithelial tumors, including cancer. Hypothesizing that the major difference between the outcome of the vaccine in preclinical models and in clinical trials is likely to be the high level of immune suppression in cancer patients, we began to develop models and MUC1 vaccines for cancer prevention in patients at risk, before immune suppression develops. We determined first that the tumor form of MUC1 was expressed on early premalignant lesions as well and chose premalignant colonic polyps as the first setting for testing the preventative vaccine. Data will be reviewed from a published feasibility study confirming immunogenicity and safety of the MUC1 vaccine in healthy individuals at risk for colon cancer. Data will then be presented from a recently completed unpublished randomized, double blind placebo controlled multi-center prophylactic MUC1 vaccine trial in the same patient population, those with a history of advanced colonic polyps and therefore at increased risk of developing colon cancer.

Citation Format: Olivera (Olja) J. Finn. Tumor-associated antigen MUC1 vaccine for colon cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY17-03.
Abstract 35: Acceptability and Perceived Impact of New Pediatric Patient Navigation Program in Rural Rwanda
Authors: Nguyen Cam , Uwamahoro Pacifique , Benemariya Esperance , Nsanzimana Oscar , Mujyuwisha Louis , Buswell Lori , Lehmann Leslie , Shyirambere Cyprien
Published: July 2021

Purpose: Patient navigation (PN) can promote timely access to care and create seamless flow for patients through the care continuum. PN strategies have not been widely studied in low-income countries or among pediatric cancer patients. We report preliminary acceptability and perceived impact among caregivers and healthcare providers of a new pediatric PN program at a rural hospital in Rwanda.

Methods: From March 2020, patients diagnosed with nephroblastoma were supported by a trained navigator who conducted in-depth education for caregivers, coordinated all appointments, and proactively identified and addressed barriers to care. Caregivers were surveyed and interviewed at the end of their child's treatment; a focus group discussion (FGD) was held with providers six months after implementation. Interviews and FGD were conducted in Kinyarwanda, transcribed and translated to English. Descriptive statistics and the framework method were used to analyze survey and qualitative data, respectively.

Results: At the time of analysis, five patients enrolled in PN had completed treatment. All five caregivers were surveyed; three interviewed. Five providers participated in the FGD. Caregivers found PN helpful in understanding the diagnosis and treatment plan, providing emotional support, and linking them to various providers. Providers observed that treatment processes for nephroblastoma patients have become “smoother,” noting increased adherence to treatment appointments, better care coordination and improved advocacy for social support. While some clinicians worried frequent communications with the navigator would be a burden, caregivers viewed them as a source of motivation to continue treatment, despite numerous challenges. Participants suggested PN be expanded to other diagnoses.

Conclusion: Early data from end-users of our new pediatric PN program demonstrated high acceptability. Clinicians highlighted specific process challenges that were resolved with PN; caregivers appreciated the continuous logistical and emotional support. Further analyses will evaluate the impact of PN on outcomes and expansion of the program to other diagnoses.

Citation Format: Cam Nguyen, Pacifique Uwamahoro, Esperance Benemariya, Oscar Nsanzimana, Louis Mujyuwisha, Lori Buswell, Leslie Lehmann, Cyprien Shyirambere. Acceptability and Perceived Impact of New Pediatric Patient Navigation Program in Rural Rwanda [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 35.
Abstract 78: Breast Cancer in Kumasi: Recent Progress
Authors: Kyei Ishmael ,   International Center For The Study Of Breast Cancer Subtypes Icsbcs Collaborators, Newman Lisa , Davis Melissa
Published: July 2021

Purpose: Breast cancer is the most common malignancy in Ghanaian women and the leading cause of cancer mortality. There have been significant improvements in the management of breast disease over the years through various partnerships and interventions. This work set out to assess one such intervention, led by the International Center for the Study of Breast Cancer Subtypes (ICSBCS) and its impact on the improved management and outcomes of breast cancer.

Methods: The study was conducted at the Komfo Anokye Teaching Hospital from January 2013 to December 2019. Patients with confirmed diagnosis of breast cancer were retrospectively assessed for presentation, mode of tissue diagnosis, immunohistochemistry and staging.

Results: Three Hundred and eleven(311) breast cancer patients were recruited. Only Sixty eight(68)patients were above 60 years. Ninety five percent(95%) of patients were diagnosed by core needle biopsy, a newly implemented modality. Hormone receptor positivity was 30%. Stage III and IV disease accounted for 72% of cases

Conclusion: Significant improvements through ICSBCS training and assistance, led to better core needle biopsy practices and immunohistochemistry, both of which are necessary for treatment decision making, Late stage at presentation still remains a challenge in the management of breast cancer.

Citation Format: Ishmael Kyei, International Center For The Study Of Breast Cancer Subtypes Icsbcs Collaborators, Lisa Newman, Melissa Davis. Breast Cancer in Kumasi: Recent Progress [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 78.
Abstract 81: Studying Ghanian Cancer Genomes Using Cell-free DNA
Authors: Ahuno Samuel , Doebley Anna-Lisa , Ahearn Thomas , Yarney Joel , Titiloye Nicholas , Hamel Nancy , Adjei Ernest , Clegg-Lamptey Joe-Nat , Edusei Lawrence , Awuah Baffour , Song Xiaoyu , Vanderpuye Verne , Abubakar Mustapha , Duggan Maire , Stover Daniel , Nyarko Kofi , Bartlet John , Aitpillah Francis , Ansong Daniel , Gardner Kevin , Bowcock Anne , Caldas Carlos , Foulkes William , Wiafe Seth , Wiafe-Addai  , Garcia-Closas Montserrat , Kwarteng Alexander , Ha Gavin , Figueroa Jonine , Polak Paz ,   On Behalf Of Ghana Breast Health Study Team
Published: July 2021

Purpose: Analysis of cell free DNA could provide a rapid and non-invasive approach to detect cancer and provide new molecular insights in many African countries where expert pathology is lacking. Hence, we tested whether whole-genome sequencing of cfDNA (WGS-cfDNA) could identify somatic alterations that drive breast cancer.

Methods: We conducted a pilot on 15 Ghanaian women (median age 49.5 years) recruited as part of the Ghana Breast Health Study. cfDNA was extracted and subjected to WGS at 30x and 0.1x. ichorCNA software was used to predict copy number alterations and ctDNA fractions.

Results: We found extensive amplification and deletion of multiple chromosomal regions including those with oncogenes and tumor suppressor genes associated with breast cancer. Similar copy number alterations for selected breast cancer genes were observed with 0.1x and 30x cfDNA-WGS with increasing concordance between the two instruments as the ctDNA fraction increases. We observed a high frequency (>50%) of copy number gain in 3/5 regions and potential target genes for the amplification (chr8p11-12 [ZNF703] n=8, 53.3%; chr8q24.2 [MYC] n=9, 60%; chr19q12 [CCNE1] n=9, 60%), which were in agreement to previous observations among African-American (AA) ancestry compared to European-American (EA) ancestry in TCGA datasets.

Conclusion: Our data provided evidence that ctDNA-based genomic studies are possible and ctDNA analysis could be a tool for future molecular oncology studies in Africa for cancer etiology, surveillance and clinical trials.

Citation Format: Samuel Ahuno, Anna-Lisa Doebley, Thomas Ahearn, Joel Yarney, Nicholas Titiloye, Nancy Hamel, Ernest Adjei, Joe-Nat Clegg-Lamptey, Lawrence Edusei, Baffour Awuah, Xiaoyu Song, Verne Vanderpuye, Mustapha Abubakar, Maire Duggan, Daniel Stover, Kofi Nyarko, John Bartlet, Francis Aitpillah, Daniel Ansong, Kevin Gardner, Anne Bowcock, Carlos Caldas, William Foulkes, Seth Wiafe, Wiafe-Addai, Montserrat Garcia-Closas, Alexander Kwarteng, Gavin Ha, Jonine Figueroa, Paz Polak, On Behalf Of Ghana Breast Health Study Team. Studying Ghanian Cancer Genomes Using Cell-free DNA [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 81.