bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract CT264: Clinical phase II study of SCO-101 - an inhibitor of SRPK1 and ABCG2 - restoring sensitivity to FOLFIRI in metastatic FOLFIRI resistant colorectal cancer patients
Authors: Vestlev Peter Michael , Roest Nicklas L. , Schou Jakob HV , Stenvang Jan , Brünner Nils
Published: September 2020

The purpose of the phase II study is to determine safety, tolerability, MTD and efficacy of SCO-101 in combination with FOLFIRI in patients with FOLFIRI resistant metastatic colorectal cancer. SCO-101 is a low molecular weight molecule (Acidic di-aryl urea). Preclinical studies have shown that it inhibits the SRPK1 kinase which phosphorylates and thereby activates proteins involved in the regulation of alternative splicing. It also degrades the ABCG2 drug efflux pump to which irinotecan (SN38) is a substrate. SCO-101 has successfully passed 4 clinical phase I studies in healthy volunteers and demonstrated to be a safe oral drug with very limited toxicity and good PK parameters. It reverses irinotecan- and several other types of anti-cancer drug resistance in in vitro and in vivo preclinical cancer models. The clinical phase II study: An open-label, non-randomized, prospective study, enrolling patients with acquired FOLFIRI resistant metastatic colorectal cancer. The study consists of two parts: -Part 1 is a dose escalation part based on a traditional 3+3 design. Increasing doses of SCO-101 are investigated in combination with a fixed, patient specific, dose of FOLFIRI. The primary objectives of part 1, is to determine the safety- and toxicity profile and the MTD of SCO-101. The MTD will be the recommended dose of SCO-101 for part 2 (RDP2); -Part 2 is the efficacy part, where up to 25 patients (Simons Two Stage Design) receive the SCO-101 RDP2 in combination with FOLFIRI. Primary objectives are to determine the safety- and toxicity profile and assess objective response rates. A number of potential biomarkers for SCO-101 efficacy will be evaluated. Approval for the study has been obtained and the study will start recruiting patients primo 2020. SCO-101 has two unique mechanisms of action. No other drugs have been presented that inhibits the SRPK1 kinase. Several published preclinical studies have associated high SRPK1 activity with progression of cancer including development of cancer drug resistance. SCO-101 is also the first drug described that degrades the ABCG2 drug efflux pump. If a positive signal is obtained in the clinical study, we will continue with a randomized clinical design allowing for time-dependent end-points, e.g. PFS and OS.

Citation Format: Peter Michael Vestlev, Nicklas L. Roest, Jakob HV Schou, Jan Stenvang, Nils Brünner. Clinical phase II study of SCO-101 - an inhibitor of SRPK1 and ABCG2 - restoring sensitivity to FOLFIRI in metastatic FOLFIRI resistant colorectal cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT264.
Abstract DDT02-04: GDC-9545: Discovery of an oral estrogen receptor antagonist, degrader, and immobilizer for the treatment of ER+ breast cancer patients
Authors: Wang Xiaojing , Wang Xiaojing
Published: September 2020

GDC-9545: Discovery of an orally bioavailable pure antiestrogen for the treatment of ER+ breast cancer patients. Breast cancer affects one out of every eight women in their lifetime making it the most frequently occurring cancer among women. Mortality remains high with more than 40,000 of women expected to die of breast cancer in 2019 in the U.S alone. Approximately 70% of all breast cancer expresses estrogen receptor alpha (ERα), making it a prime target for the treatment of breast cancer. Despite effective endocrine therapies, many patients eventually relapse and become resistant to standard of care treatments. These endocrine resistant tumors often continue to depend on ERα for growth and survival, as evidenced by their sensitivity to the selective estrogen receptor antagonist and degrader, fulvestrant. However, fulvestrant is limited by its pharmaceutical and pharmacokinetic properties and its intramuscular route of administration to achieve sufficient target occupancy. Consequently, selective ERα ligands with desirable mechanisms of action and superior drug properties were sought after, allowing consistent and rapid achievement of therapeutic exposure. We have reported previously of our first and second generations of orally available ERα ligands, GDC-0810 and GDC-0927 respectively. Targeting a pure antiestrogen profile and guided by co-crystal structures, we identified a structurally distinct scaffold from these first two generations. Fine-tuning the physiochemical properties while balancing potency and efficacy culminated into a third generation development candidate GDC-9545. GDC-9545 immobilizes ERα to achieve full antagonism and degradation. It inhibits tumor growth or causes tumor regression in patient derived xenograft mouse models. It is orally bioavailable and has high safety margins in preclinical species. GDC-9545 is currently in active clinical testing.

Citation Format: Xiaojing Wang, Xiaojing Wang. GDC-9545: Discovery of an oral estrogen receptor antagonist, degrader, and immobilizer for the treatment of ER+ breast cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr DDT02-04.
Abstract LB-008: Patient derived organoids: Bringing the "patient in the lab" for pre-clinical and clinical development
Authors: Mullenders Jasper , Buijs Annemarie , Van Maanen Inge , Piani Carol , Mardpour Soura , Clevers Hans , Vries Rob , Boj Sylvia
Published: September 2020

Pre-clinical disease models are essential for the development of novel therapies and help better understand the molecular processes. In recent years, a novel groundbreaking technology to generate patient specific in vitro cultures based on adult stem-cell organoids, has gained widespread interest for the development of new therapies and as a predictive diagnostic tool. ASC-organoids can be generated at high efficiency from both healthy and diseased tissue (resections as well as biopsies) including most carcinomas. These patient derived cultures can be expanded for prolonged periods of time while maintaining many properties of the tissue they were derived from. At HUB, we have created comprehensive ‘living biobanks' from tumors of different origin like colon, lung, breast, pancreas and ovary. These biobanks have been characterized at the genetic and transcriptional level. These analyses have shown that our ‘living biobanks' capture disease heterogeneity at the genetic and molecular level. Because organoids can be expanded long term, drug screening is feasible in these models. HUB has developed procedures for (high-throughput) compound screening in organoids including small molecules and biologics. In this setting, organoids have been used to identify novel targets, identify lead compounds and stratify potential responders based on their genetic or molecular profile. Recent advances in the field of immuno-oncology have revolutionized the treatment for cancer patients. Despite of the improvements and due to the complex and highly regulated nature of the immune system, treatment does not have a similar effect on all tumors. We have created a co-culture model of tumor derived organoids and immune cells. In these co-cultures, the cytotoxic effect of the immune cell on the tumor can be measured in a reproducible and quantitative manner. Currently we are expanding existing co-culture models to incorporate different immune cells and organoid tumor types. In addition, organoids can serve as a patient avatar in clinical development or diagnostics. In this setting, organoids could add a functional test for therapy response in a patient centered setting providing a unique tool for personalized medicine.

Citation Format: Jasper Mullenders, Annemarie Buijs, Inge Van Maanen, Carol Piani, Soura Mardpour, Hans Clevers, Rob Vries, Sylvia Boj. Patient derived organoids: Bringing the "patient in the lab" for pre-clinical and clinical development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-008.
Abstract LB-021: Focal adhesive kinase inhibitor IN10018 sensitizes KRAS mutant cancer and overcomes drug resistance of KRAS G12C inhibition
Authors: Zhang Baoyuan , Zhang Yan , Zhang Jiangwei , Liu Ping , Jiao Bo , Wang Zaiqi , Ren Ruibao
Published: September 2020

KRAS mutation is found in around 20-30% of human cancer. Previously, lack of targeting therapy limited the treatment outcomes. Recently, KRAS G12C inhibitors like AMG510, MRTX849, and MRTX1257 were developed and exhibited promising therapeutic outcomes targeting the mutation. However, a considerable amount of cases showed less sensitivity, indicating either intrinsic or adaptive resistance mechanisms. Other reports and our own data exhibited that Focal Adhesive Kinase (FAK) inhibition showed good treatment effects to KRAS mutant cancer. Interestingly, TCGA data analysis reveal that FAK mRNA expression level is significantly higher in KRAS mutant tumors. Considering that FAK is one predominant target for cancer treatment resistance, we hypothesize that FAK is one of mediator leading to resistance mechanism of KRAS G12C inhibition. To explore our hypothesis, we employed high potent FAK inhibitor IN10018, which is being tested in phase I clinical trial for different cancer types. First, we found that IN10018 is active in a series of KRAS mutated cancer xenograft models. The compound sharply decreased the level of phosphoFAK Y397, a direct marker for FAK activity. Then we investigated whether combination of IN10018 with KRAS G12C inhibitors can show synergic effects in vitro and in vivo. IN10018 in combination with either AMG510 or MRTX1257 showed better effects in killing KRAS G12C cancer cells than each single treatment. More importantly a significant synergy between IN10018 with KRAS G12C inhibitors against KRAS mutated cancer cell lines was observed in vivo. Further evidence showed that KRAS G12C inhibition can significantly increase the expression of phosphoFAK Y397, suggesting a possible underlying mechanism of resistance to KRAS G12C inhibitors. IN10018 significantly decreased the upregulated FAK Y397 phosphorylation in the combination treatments, underlying the mechanism of synergy between the two inhibitors. Our results indicate that KRAS G12C cancer patients can be better treated by the combination of IN10018 with KRAS G12C inhibitor.

Citation Format: Baoyuan Zhang, Yan Zhang, Jiangwei Zhang, Ping Liu, Bo Jiao, Zaiqi Wang, Ruibao Ren. Focal adhesive kinase inhibitor IN10018 sensitizes KRAS mutant cancer and overcomes drug resistance of KRAS G12C inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-021.
Abstract LB-047: CHMP5 dependency is a therapeutic vulnerability of T cell acute lymphoblastic leukemia
Authors: Umphred-Wilson Katharine , Adoro Stanley
Published: September 2020

T-cell acute lymphoblastic leukemia (T-ALL) is a very aggressive hematologic malignancy that results from the transformation of immature T-cell progenitors. Aberrant cell growth and proliferation is sustained by strong oncogenic drivers, notably NOTCH1 and MYC, whose activation is present in more than half of all T-ALL cases. However, although it is known that post-translational modifications, such as ubiquitination by the E3-ligase FBXW7, regulate NOTCH1 and MYC protein stability and activity, regulatory proteins involved in their stability remain unestablished. The Charged multivesicular body protein 5 (CHMP5), an accessory protein of the ESCRT (endosomal sorting complex required for transport) pathway, has been shown to regulate the stability of client proteins in thymocytes through the recruitment of de-ubiquitinating enzymes. Here, we report that CHMP5 protein is not only highly expressed in T-ALL cells, but also promotes the stability of transactivating intracellular NOTCH1 (ICN1) and MYC. We found that depletion of CHMP5 significantly reduced the abundance of ICN1 and MYC, and the transcription of their target genes in vitro, as well as suppressed the development of T-ALL in vivo in a murine model of NOTCH1 driven T-ALL. Additionally, loss of CHMP5 restored T-ALL cell susceptibility to chemotherapeutic agents, including glucocorticoids and gamma secretase inhibitors, resistance to which contributes to disease relapse in patients. We further reveal CHMP5 as an adaptor protein required to orchestrate T-ALL client protein deubiquitination and stability. Altogether, our data suggest that CHMP5 is a non-oncogenic dependency of T-ALL and its depletion may be an effective therapeutic strategy for T-ALL.

Citation Format: Katharine Umphred-Wilson, Stanley Adoro. CHMP5 dependency is a therapeutic vulnerability of T cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-047.
Abstract LB-077: Dendritic cell dysfunction precedes tumor formation during pancreatic oncogenesis
Authors: Lin Jeffrey H. , Vonderheide Robert H.
Published: September 2020

Dysfunction of type 1 conventional dendritic cells (cDC1s) - the dendritic cell subtype crucial for spontaneous anti-tumor T cell immunity - has long been hypothesized to develop secondarily to invasive cancer. Here, we reveal that cDC1 dysfunction instead develops in the earliest stages of cancer development upon formation of preinvasive pancreatic intraepithelial neoplasias (PanINs) in the KrasG12D Trp53R172H Pdx1-Cre-driven (KPC) mouse model of pancreatic ductal adenocarcinoma. This results in systemically increased cDC1 apoptosis and insufficient upregulation of T cell-polarizing cytokines during cDC1 maturation. CD8+ T cell activation following vaccination is subsequently impaired in PanIN- and tumor-bearing mice. Yet, combination therapy with CD40 agonist and Flt3 ligand in tumor-bearing mice returns cDC1 abundance to normal levels and induces an IFNg response signature, repairing cDC1 maturation and restoring full CD8+ T cell activation. This study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation while elaborating therapeutically tractable strategies towards cDC1 repair.

Citation Format: Jeffrey H. Lin, Robert H. Vonderheide. Dendritic cell dysfunction precedes tumor formation during pancreatic oncogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-077.
Abstract LB-086: CD3 MOSPD2 bi specific antibody significantly prolongs survival in a model of metastatic human cervical cancer without any evidence of toxicity
Authors: Yacov Niva , Propheta-Meiran Oshrat , Kafri Pinhas , Salem Yaniv , Mendel Itzhak , BREITBART EYAL
Published: September 2020

Introduction: We have previously showed that motile sperm domain-containing protein 2 (MOSPD2), is highly expressed in multiple solid tumors and cancer cell lines but has low/undetectable levels in healthy tissues, implying that MOSPD2 can be an effective target for directed killing of tumor cells. We developed CD3xMOSPD2 bi-specific IgG antibodies (BsAb) that induced T-cell activation and yielded profound death of target tumor cells in-vitro.

Experimental procedure: NSG mice were injected subcutaneously with the metastatic cervical cancer HeLa cell line (day 0). Freshly isolated human PBMC were transferred I.P when tumors volume reached an average of 150mm3 (day 29). Subsequently, mice were treated I.V with control IgG antibody or CD3xMOSPD2 BsAb and monitored for survival. To assess in-vivo T-cell activation, serum collected 6hr after first antibody treatment was analyzed for cytokines level.

Results: Treatment with CD3xMOSPD2 BsAb, significantly increased serum concentration of IFN-γ, IL-6 and TNF-α compared with control IgG-treatment. Strikingly, by day 65, survival rate of CD3xMOSPD2 BsAb treated mice was 90% compared with only 10% in the control IgG-treated group (n=9-10; p=0.00106). No evidence of toxicity or off target activity was detected.

Conclusions: Our data show that CD3xMOSPD2 bi-specific antibody induces T-cell activation in-vivo and significantly extends the survival of mice carrying established metastatic cervical cancer. These results highlight the potential of bi-specific mediated immuno-oncology therapy for the treatment of MOSPD2-positive metastatic solid tumors.

Citation Format: Niva Yacov, Oshrat Propheta-Meiran, Pinhas Kafri, Yaniv Salem, Itzhak Mendel, EYAL BREITBART. CD3 MOSPD2 bi specific antibody significantly prolongs survival in a model of metastatic human cervical cancer without any evidence of toxicity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-086.
Abstract LB-098: The anti-tumor activity of the KRAS G12C inhibitor MRTX849 is augmented by cetuximab in CRC tumor models
Authors: Hallin Jill , Calinisan Andrew , Hargis Lauren , Aranda Ruth , Engstrom Lars D. , Briere David M. , Marx Matthew A. , Olson Peter , Christensen James G.
Published: September 2020

The ability to develop effective therapies for KRAS mutant cancers has remained elusive despite decades of research. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor presently under evaluation in clinical trials. MRTX849 inhibits only inactive GDP-bound KRASG12C, a mutation known to be dependent on nucleotide cycling and extrinsic factors which regulate the activation state of KRAS. Preclinical and early clinical data suggest KRASG12C inhibitors induce tumor regression/response in a subset of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models and patients. Previous work in tumor xenograft models demonstrated activation of pathways upstream or downstream of KRAS through additional mutations or relief of feedback inhibition can limit the single agent activity of MRTX849 in the less responsive tumors. These data indicated that activation of receptor tyrosine kinases (RTKs) through relief of feedback inhibition was one mechanism implicated in modulating the response to MRTX849. As KRAS G12C mutations are present in ~4% of colon cancer, MRTX849 was further evaluated in CRC models to identify combination strategies that might optimize anti-tumor activity. A range of responses to single agent MRTX849 were observed across cell line and patient-derived xenograft (PDX) models. The combination of MRTX849 plus cetuximab demonstrated the best anti-tumor activity in multiple models. The combination of MRTX849 and cetuximab demonstrated increased KRASG12C modification and MAPK pathway inhibition suggesting these therapies converge to more fully inhibit KRASG12C. Despite the fact that cetuximab-based therapy is contra-indicated for KRAS-mutant CRC, these data suggest co-targeting EGFR and KRAS may more comprehensively inhibit KRAS mediated signaling and more effectively treat a subset of CRC patients with KRASG12C-mutant cancers.

Citation Format: Jill Hallin, Andrew Calinisan, Lauren Hargis, Ruth Aranda, Lars D. Engstrom, David M. Briere, Matthew A. Marx, Peter Olson, James G. Christensen. The anti-tumor activity of the KRAS G12C inhibitor MRTX849 is augmented by cetuximab in CRC tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-098.
Abstract LB-149: Serum thymidine kinase 1 levels predict prostate cancer-specific survival
Authors: Murtola Teemu J. , Raittinen Paavo , Tammela Teuvo
Published: September 2020

Background: Thymidine kinase 1 (TK1) is an enzyme involved in DNA synthesis. Thymidine kinases phosphorylate thymidine as part of the DNA synthetic pathway. TK1 expression is a marker of active cellular proliferation; intracellular concentrations are low during the G0/G1 phases of the cell cycle, increasing during the S/G2 phases. Previous studies have suggested that serum TK1 levels could be used as marker for presence of prostate cancer (PCa). Here, we evaluated whether serum TK1 levels could predict risk of PCa prognosis. Materials and Methods: The study population included 40 men with clinically defined T1/T2NxM0 PCa and 43 men with de novo metastatic cancer (M1) at diagnosis confirmed by bone scan imaging. All men were diagnosed and treated at the Tampere University Hospital between 2000-2010. All men provided a serum sample at the time of diagnosis. Information on deaths and causes of death were obtained from national causes of death registry. Serum TK1 concentrations were determined using the AroCell TK210 ELISA kit. Cox regression and Kaplan-Meier Curves with adjustment for tumor risk group (Gleason-grade, TNM stage and PSA level) were used to evaluate the risk of PCa death in relation to TK1 levels (median or below vs. above median). ROC analyses were used to evaluate the predictive accuracy of PSA, TK1 and their combination. Results: M1 cases were older than M0 cases; median age 72 vs 62 years, respectively. M1 cases were mainly managed with androgen deprivation therapy, whereas M0 cases were most often managed with radical prostatectomy. Median serum TK1 levels were significantly higher among M1 cases compared to M0 cases (p for difference 0.001). In the combined study population, serum TK1 levels were a significant predictor of PCa-specific (HR 8.33, 95% CI 2.05-33.88) and overall mortality (HR 5.53, 95% CI 1.93-15.85) after adjustment for established prognostic factors including tumor risk group. Kaplan-Meier survival curves defined by TK1 level started to differ within 24 months from PCa diagnosis. In ROC analyses TK1 alone or in combination with PSA was no more accurate than PSA alone in predicting PCa death. Conclusion: The proliferation biomarker TK1 in serum predicted survival after PCa diagnosis, demonstrating independent predictive value over established clinical risk factors. If confirmed in further and larger studies, this biomarker could be incorporated in PCa risk stratification when selecting optimal treatment and surveillance schedule.

Citation Format: Teemu J. Murtola, Paavo Raittinen, Teuvo Tammela. Serum thymidine kinase 1 levels predict prostate cancer-specific survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-149.
Abstract LB-159: The association of alveolar lipid laden macrophages with inflammatory cytokines in electronic cigarette users
Authors: Song Min-Ae , Shields Peter G. , Freudenheim Jo L. , Brasky Theodore M. , McElroy Joseph P. , McElroy Joseph P. , Reisinger Sarah A. , Weng Daniel Y. , Ren Rongqin , Eissenberg Thomas , Wewers Mark D. , Shilo Konstantin
Published: September 2020

Introduction: Lipid laden macrophages (LLM) from lung bronchoscopies have been identified as characteristic for some patients with e-cigarette (e-cig) or vaping product use associated lung injury (EVALI). While vaping with THC oils containing vitamin E acetate is thought to have caused the outbreak, there is a subset of the EVALI cases who reported vaping only with nicotine-containing e-cigs. A recent animal study showed that propylene glycol (PG) and vegetable glycerin altered lipid homeostasis and induced LLM. In addition to the associations with EVALI, understanding the health effects of vaping with e-cigs in general needs additional investigation. Objective: We examined alterations in alveolar lipid homeostasis comparing e-cig users to cigarette smokers and never-smokers. Further, we determined the association of LLM with inflammatory cytokines. Methods: LLMs, inflammatory cell counts, and cytokines were determined in bronchial alveolar fluids (BAL) from a cross-sectional study of 62 volunteer subjects, age 21-45. Participants who were e-cig users were either never-smokers or former smokers. Cigarette smoking and e-cig use were confirmed by biomarkers of exposure, including lung and urine cotinine and 3-hydroxycotinine and urine anatabine, nicotelline, and PG. Results: High LLM counts were found in the lungs of almost all smokers and about half of the e-cig users, but not in any never-smokers (P<0.001). LLMs were significantly correlated with the inflammatory cytokines IL-4 and IL-10 in e-cig users (P=0.01). Smoking history, including cigarettes per day and biomarkers of exposure, e-cig use history, and gender were not associated with LLMs (all P>0.05). LLMs were not related to THC exposure. Discussion: This is the first report comparing LLMs in the lungs of e-cig users with smokers and never-smokers. LLMs were found in lungs of both smokers and a portion of e-cig users. Given their presence among smokers, they are not likely to be useful as a marker identifying those with EVALI. However, LLMs may be one of the markers for specific disease risks associated with e-cig usage, but not smoking.

Citation Format: Min-Ae Song, Peter G. Shields, Jo L. Freudenheim, Theodore M. Brasky, Joseph P. McElroy, Joseph P. McElroy, Sarah A. Reisinger, Daniel Y. Weng, Rongqin Ren, Thomas Eissenberg, Mark D. Wewers, Konstantin Shilo. The association of alveolar lipid laden macrophages with inflammatory cytokines in electronic cigarette users [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-159.
Abstract LB-210: Chemotherapy promotes metastasis through extracellular vesicle secretion
Authors: Wills Carson A. , Sundstrom Jeffrey , Wang Hong-Gang
Published: September 2020

Neoadjuvant chemotherapy treatment is the gold standard for children and adults with intermediate- to high-risk tumors. However, a subset of patients develop distant metastases following treatment, and evidence suggests that chemotherapy itself may promote metastasis in some patients. Indeed, utilizing xenograft mouse model of human triple-negative breast cancer, we confirm that treatment with the chemotherapeutic agent Doxorubicin decreases primary tumor growth while promoting pulmonary metastasis. The purpose of this research is to understand how chemotherapy treatment regulates tumor-derived exosomes, extracellular vesicles that are secreted by all cells and that function in cellular communication through the horizontal transfer of biologically-active molecules. Specifically, our goal is to determine how exosomes derived from chemotherapy-treated tumor cells, or ‘chemoexosomes,' regulate tumor metastasis in order to develop more effective chemotherapeutic options for cancer patients. Utilizing models of both breast cancer and pediatric neuroblastoma, we demonstrate that sublethal doses of DNA-damaging chemotherapeutic agents significantly enhance exosome secretion compared to vehicle control. Xenografted mice treated with exosomes derived from chemotherapy-treated cells demonstrate a significant acceleration in metastasis with no increase in primary breast tumor growth compared to mice treated with exosomes derived from control-treated cells or saline. Although chemoexosomes do not enhance tumor cell migration or invasion in vitro, they demonstrate tumor type-specific preferential organotropic localization to the most common sites of tumor metastasis in vivo. Mice treated with chemoexosomes prior to tail-vein injection of either neuroblastoma or breast tumor cells demonstrate a significant increase in metastatic tumor burden compared to mice pre-treated with control exosomes or saline. Through proteomic analysis, we identified differentially-expressed exosomal proteins upregulated by chemotherapy treatment. Utilizing CRISPR-Cas9-mediated gene knockout, we identified a component of the complement pathway upregulated in chemoexosomes that is critically involved in exosome-mediated metastasis. Taken together, this research proposes a novel mechanism of chemotherapy-induced metastasis by which organ-specific uptake of exosomes derived from chemotherapy-treated cells primes the pre-metastatic niche in order to create a favorable environment for metastatic tumor growth.

Citation Format: Carson A. Wills, Jeffrey Sundstrom, Hong-Gang Wang. Chemotherapy promotes metastasis through extracellular vesicle secretion [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-210.
Abstract LB-220: Functional consequences of aberrant alternative splicing in embryonal tumor with multilayered rosettes
Authors: AbouRaya Dina Hesham , El-Naggar Shahenda
Published: September 2020

Embryonal tumor with multilayered rosettes (ETMR) is an aggressive and rare variant of embryonal brain tumors. Amplification of C19MC microRNA cluster and expression LIN28 are distinctive features of ETMR. Despite the increasing efforts to decipher ETMR, the biology remains poorly understood. To date, the role of aberrant alternative splicing in ETMR is not thoroughly investigated. In the current study a comprehensive analysis was performed on published unprocessed RNA-seq reads of tissue- matched ETMR (SRP032476), and fetal controls from the Human Developmental Biology Resource (HDBR) (E-MTAB-4840) datasets. Gene expression was quantified in samples using kallisto/sleuth pipeline. For the alternative splicing analysis, reads were mapped to the genome (hg38) using STAR. Identification and quantification of alternative splicing events (skipped exon, alternative 5′ and 3′splice sites, mutually exclusive exons, multi Exons Skip and retained intron) were carried out using SplAdder. Functional enrichment analysis for the differentially expressed and the differentially spliced genes was subsequently performed using Metascape. All statistical values reported were corrected for multiple hypothesis testing by Benjamini-Hochberg false discovery rate (q-values).The expression analysis revealed a total of 2205 differentially expressed genes (DEGs) between ETMR and fetal controls while 2446 showed differential alternative splicing patterns. DEGs with significant alternative splicing events were identified to be involved in ubiquitin mediated proteolysis, endocytosis, RNA transport, regulation of actin cytoskeleton pathways as well as histone modification. Interestingly, DEGs with intron retention events were involved in various signaling pathways including TGF-beta signaling pathway, MAPK signaling pathway and ErbB signaling pathway. These findings highlight the role of defective alternative splicing in shaping ETMR tumor landscape, and the identified pathways constitute potential therapeutic targets.

Citation Format: Dina Hesham AbouRaya, Shahenda El-Naggar. Functional consequences of aberrant alternative splicing in embryonal tumor with multilayered rosettes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-220.
Abstract LB-221: Aggresome-based classification is a promising prognostic marker for pediatric choroid plexus tumors
Authors: Amer Nada , Taha Hala , Hesham Dina , Mahmoud Noura , Elayadi Moatasem , Mossab Amal , Youssef Ayda , Elbeltagy Mohamed , Zaghloul Mohamed Saad , Azziz Ahmad Abdel , El-Naggar Shahenda
Published: September 2020

Protein misfolding and aggregation result in proteotoxic stress, and underlie the pathogenesis of many diseases. To overcome proteotoxicity, cells compartmentalize misfolded and aggregated proteins in different inclusion bodies. Aggresome is a paranuclear inclusion body that functions as a storage compartment for misfolded proteins. Our previous work revealed the presence of aggresomes in pediatric choroid plexus tumors (CPT). CPTs are rare neoplasms comprised of three pathological subgroups; choroid plexus carcinoma (CPC), a grade III tumor, atypical choroid plexus papilloma (ACPP), a grade II tumor, and choroid plexus papilloma (CPP), a grade I tumor. In the current study, we aimed to investigate the prognostic value of aggresomes-positivity and if it could be used to improve the disease subclassification. Forty two pediatric CPT tumor samples were stratified into two molecular subgroups; Cluster “A", and “B”, using Illumina Infinium Methylation EPIC BeadChip array. Kaplan Meier analysis showed that “cluster B” is associated with significantly shorter overall survival (OS) and event free survival (EFS) with P= 0.008 and P =0.007 respectively. Aggresomes were detected in 64.2% of samples using immunohistochemistry and they were distributed among different pathological and molecular subgroups. The presence of aggresomes significantly correlated with patient outcome in both OS (P = 0.057) and EFS (P = 0.051). The survival-based cutoff determination was performed using various percentages of aggresomes; ranging from 10% to 50%. Aggresome presence maintained significance at all cutoffs, yet the 25% cutoff had the highest impact in OS and EFS (P = 0.001). Moreover, the classification based on the 25% cutoff concurred with the methylation signature of low-risk “A” and high-risk “B” clusters. Hence, the detection of aggresomes in CPTs provides a new prognostic marker supporting histopathological tumor classification.

Citation Format: Nada Amer, Hala Taha, Dina Hesham, Noura Mahmoud, Moatasem Elayadi, Amal Mossab, Ayda Youssef, Mohamed Elbeltagy, Mohamed Saad Zaghloul, Ahmad Abdel Azziz, Shahenda El-Naggar. Aggresome-based classification is a promising prognostic marker for pediatric choroid plexus tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-221.
Abstract LB-329: Pancancer proteomic investigation identifies overexpressed kinases as novel cancer dependent targets
Authors: Elmas Abdulkadir , Molina-Sanchez Pedro , Tharakan Serena , Jaladanki Suraj , Liu Tao , Lujambio Amaia , Huang Kuan-lin
Published: September 2020

Dysregulated oncogenic signaling is a key hallmark of cancer. Protein kinase alterations, including genomic mutations and copy-number amplifications, are known druggable targets in multiple cancer types. Thus, kinase inhibitor drugs act on protein and direct observation of protein/phospho-level overexpression may reveal new treatment opportunities. Herein, we developed and applied a new algorithm, OPPTI, to provide a catalog of overexpressed kinases across 10 cancer types using curated global mass spectrometry proteomic data of 1,071 cases. Aside from overexpressed proteins through genomic mutations, amplifications, or fusions, including ERBB2, AKT2, and EGFR, kinase overexpression also occurred in cancers without genomic-level alterations, such as CDK6 in hepatocellular carcinoma (HCC), FGFR1/2 in ovarian cancer, and PDGFRA in both gastric cancer and lung adenocarcinoma. Integrating cancer-cell dependency data, we further identified 38 new cancer vulnerability targets overexpressed in >10% of the patient cohorts, including TK1 in breast and gastric cancers, NRBP2 in liver and lung cancers, and CKB in ovarian, endometrial, and colorectal cancers. A fraction of overexpressed kinases was validated by immunostainings and correlated with phosphosignaling pathway activities. Finally, we demonstrated that a subset of HCC mouse models that overexpressed PDGFRB -as detected in parallel in human HCC cohorts- could be specifically treated by a receptor tyrosine kinase inhibitor. Overall, our results suggest that proteomic-level alterations not readily observed by genomics represent cancer vulnerabilities that need to be carefully considered as potential targets for personalized treatments.

Citation Format: Abdulkadir Elmas, Pedro Molina-Sanchez, Serena Tharakan, Suraj Jaladanki, Tao Liu, Amaia Lujambio, Kuan-lin Huang. Pancancer proteomic investigation identifies overexpressed kinases as novel cancer dependent targets [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-329.
Abstract LB-352: CD4+ follicular helper-like T cells are key players in anti-tumor immunity
Authors: Ganesan Anusha Preethi
Published: September 2020

CD4+ T helper cells (TH) are central orchestrators of an efficient immune response. However, within the tumor microenvironment (TME), it is unknown what type of CD4+ TH cells or CD4 helper-derived signals are essential to generate robust CD8+ CTL and TRM anti-tumor immune responses, which are positively associated with patient prognosis.

To determine the nature of CD4+ T cells that provide ‘help' for generating robust anti-tumor CD8+ CTL responses, we profiled the transcriptomes of patient-matched CD4+ and CD8+ T cells present in the TME of treatment-naïve patients with lung cancer and analyzed them jointly using a novel approach, integrated weighted gene correlation network analysis.

We found that the follicular helper T cell (TFH) program in CD4+ T cells was strongly associated with proliferation and tissue-residency in CD8+ CTLs. Single-cell transcriptomic analysis demonstrated the presence of tumor-infiltrating TFH-like cells, a subset of which lacked CXCR5 expression but displayed superior functional properties such as provision of CD8+ ‘help', cytotoxicity and proliferation. Because these anti-tumor functions were not previously ascribed to TFH cells which are known to support B cell responses, we validated our findings using independent in vitro and in vivo approaches. Multi-parametric immunohistochemistry showed co-localization of TFH cells with CD8+ TRM cells within tumors, the density of which was positively correlated with that of TFH cells. Adoptive transfer or induction of TFH cells in mouse tumor models resulted in augmented CD8+ CTL responses and impairment of tumor growth, indicating an important role of TFH-like CD4+ T cells in anti-tumor immunity. Furthermore, tumor-infiltrating TFH-like cells expressed PD-1 and were enriched in tumors following checkpoint blockade, suggesting that they may respond to anti-PD-1 therapy in addition to CD8+ CTLs. Our findings provide insights into the molecular identity and functional status of CD4+ T cells within tumors that mount robust CTL responses and uncover potential targets for tumor immunotherapy.

Citation Format: Anusha Preethi Ganesan. CD4+ follicular helper-like T cells are key players in anti-tumor immunity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-352.
Abstract LB-379: Dominant negative PD1 armored CAR-T cells induce remission in relapsed or refractory non-Hodgkin lymphoma (NHL) patients
Authors: Yuan Yan , Huang Liansheng , Su Yang , Pu Chengfei , Ding Tianling , Xiao Xibin , Jin Lina , Cao Zhiyuan , Wu Ting , Chen Tong , Ding Luying , Zhang Xiaohong , Lan Haifeng , Wu Zhao , Xiao Lei
Published: September 2020

The chimeric antigen receptor (CAR) T cell treatment has been demonstrated as an effective therapy to treat relapsed/refractory B cell malignancy. However, tumor microenvironment influences and affects the efficacy of CAR T treatment. For example, programmed death ligand 1/2 (PDL1/2) may inhibit the CAR T cells via interaction with up-regulated programmed cell death protein 1 (PD1) after T cells activation, suppressing the tumor-killing capability of the CAR T cells. Thus, blockade of the PD1-PDL1/2 interaction may enhance the anti-tumor efficacy of CAR T therapy.Here, we generated CAR T expressed an anti-CD19 CAR molecule and a dominant-negative PD1 molecule. Compared with conventional CART cells, these “armored” CART cells showed the enhanced capability of tumor-killing and more “memory-like” phenotypes after multiple-round tumor challenging. These results suggest dominant-negative PD1 molecules may protect CART cells from exhaustion in the tumor microenvironment.Further, we reported the findings of a clinical trial for six relapsed or refractory B-cell non-Hodgkin lymphoma (NHLs) patients treated using our armored CAR T cells. These six patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the patients were infused with autologous CAR T cells range from1×106/kg to 8×106/kg. PET/CT showed significant tumor shrinkage and SUV max declines in all six patients, and the ongoing responses were monitored. The best overall response rate (ORR)was 100%. Conclusion: The results of these six patients in the clinical trial showed that our armored CAR T cells achieved the significant anti-bulky lymphoma response while causing limited and tolerated cytokine release syndrome and central nervous system toxicity. Thus, dominant-negative PD1 molecules may increase CAR T cells persistence in patients, enhancing the efficacy of CAR T cells for treating blood cancer. Finally, dominant-negative PD1 can be used as a platform technology and may be applied to other adoptive cellular immunotherapies such as TCR-T or TIL in the treatment of solid tumors. We are continuing to monitor current patients and recruit more patients for the clinical trial.

Citation Format: Yan Yuan, Liansheng Huang, Yang Su, Chengfei Pu, Tianling Ding, Xibin Xiao, Lina Jin, Zhiyuan Cao, Ting Wu, Tong Chen, Luying Ding, Xiaohong Zhang, Haifeng Lan, Zhao Wu, Lei Xiao. Dominant negative PD1 armored CAR-T cells induce remission in relapsed or refractory non-Hodgkin lymphoma (NHL) patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-379.
Comprehensive Immuno-Molecular Profiles for Liposarcoma: Roles of Programmed Death Ligand 1, Microsatellite Instability, and PIK3CA
Authors: Jeon Hyae Min , Lee Jae Seok , Kim Soo Hee , Yun Kum-Hee , Park Kyu Hyun , Jeon Min Kyung , Lee Young Han , Yoon Hong In , Suh Jin-Suck , Hur Hyuk , Kim Kyung Sik , Kim Sunghoon , Kim Seung Hyun , Kim Hyo Song
Published: September 2020

Background: Developing personalized strategies for cancer has shown good efficacies. Methods: We assessed the molecular targets programmed death ligand 1 (PD-L1), microsatellite instability (MSI), and PIK3CA. Seventy-four patients with liposarcomas who underwent curative resection were assessed for PD-L1 expression in the tumor and tumor-infiltrating lymphocytes (TILs), mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry, MSI using polymerase chain reaction, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization. Results: Seventeen (23%) cases were TIL+ (≥1 + expression) and associated with longer 5-year overall survival than those with TIL– tumors (84.4 vs. 60.8%, p = 0.007). Six (35.3%) PD-L1+ tumors were detected only in TIL+ cases, with none detected in tumor cells. Two well-differentiated liposarcomas showed MSI, one low and one high with concurrent loss of MLH1, MSH6, and PMS2. PIK3CA mutation was detected in 7 (9.5%) [exon 9 (n = 4) and exon 20 (n = 3)] and only 1 Q546K mutation was a PD-L1+ tumor. PIK3CA copy number gain was detected in 18 (24.4%) and was associated with TIL+ tumors (p = 0.045). Conclusions: Our comprehensive immuno-molecular panel suggests that liposarcoma should be categorized based on the molecular genomic subtype for precision medicine.
A new approach for improving clustering algorithms performance
Authors: Alrammahi Anfal F. N. , Aljanabi Kadhim B. S.
Published: September 2020

Clustering represents one of the most popular and used Data Mining techniques due to its usefulness and the wide variations of the applications in real world. Defining the number of the clusters required is an application oriented context, this means that the number of clusters k is an input to the whole clustering process. The proposed approach represents a solution for estimating the optimum number of clusters. It is based on the use of iterative K-means clustering under three different criteria; centroids convergence, total distance between the objects  and the cluster centroid and the number of migrated objects which can be used effectively to ensure better clustering accuracy and performance. A total of 20000 records available on the internet were used in the proposed approach to test the approach. The results obtained from the approach showed good improvement on clustering accuracy and algorithm performance over the other techniques where centroids convergence represents a major clustering criteria. C# and Microsoft Excel were the software used in the approach.
A brief review: basic coil designs for inductive power transfer
Authors: Nazieha Nanda Nadia , Hajar Yusoff Siti , Fauziah Toha Siti , Fadzlin Hasbullah Nurul , Shafina Roszaidie Amelia
Published: September 2020

The inductive power transfer (IPT) has contributed to the fast growth of the electric vehicle (EV) market. The technology to recharge the EV battery has attracted the attention of many researchers and car manufacturers in developing green transportation. In IPT charging system, the coil design is indispensable in enhancing the EV battery charging process performance. This paper starts by describing the two charging techniques; static charging and dynamic charging before further presents the IPT system descriptions. Afterwards, this paper describes a brief review of coil designs which discusses the critical factors that affect the power transmission efficiency (PTE) including their basic designs, design concepts and features merits. The discussions on the basic coil designs for IPT are of the circular spiral coil (CSC), square coil (SC), rectangular coil (RC), and double-D coil (DDC). Furthermore, the significant advantages and limitations of each research on different geometries are analyzed and discussed in this paper. Finally, this paper evaluates some essential aspects that influence the coil geometry designs in practical.