bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1324: Evaluation of KIF14 in a chemotherapeutic resistant breast cancer cell line
Authors: Cleghorn Keeley , Steding Catherine E.
Published: July 2021

The purpose of this study is to elucidate the mechanisms of KIF14 in acquired paclitaxel chemoresistance in a breast cancer cell line by evaluating its expression, activity, and regulatory network. Chemoresistance remains the single greatest cause of therapeutic failure in cancer therapeutics. Development of chemoresistance for compounds that often only suppress growth and do not eliminate tumors has been shown to correlate with more severe clinical phenotypes. Paclitaxel, the microtubule stabilizing compound, has been shown to be of particular importance in the study of chemoresistance as its therapeutic efficacy has been directly shown to be tempered by resistance. Whole transcriptome analysis of long-term chemoresistant breast cancer cells generated at Indiana State University identified a gene not previously reported to play a role in the acquired chemoresistance of breast cancer, kinesin family member 14, KIF14 (Table 1). A knockdown of KIF14 in a chemoresistant breast cancer cell line was performed using Lipofectamine™ 3000 Transfection Reagent. Western Analysis and RT- PCR was performed to confirm the expression of the gene both before and after knockdown was performed. Once expression alterations were confirmed, a proliferation assay, population doubling assay, and a colony formation assay were performed to explore the effects of the gene knockdown in response to paclitaxel treatment. Findings from these studies identify a potential role for KIF14 and microtubule dynamics in acquired chemoresistance against paclitaxel.

KIF14 sequencing analysis performed using Illumina HiSeq4000 technology in chemoresistant cellsGeneLog2 Fold Change in Resistant CellsP-valueFDRKIF141.592.83x10-154.18x10-14

Citation Format: Keeley Cleghorn, Catherine E. Steding. Evaluation of KIF14 in a chemotherapeutic resistant breast cancer cell line [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 1324.
Abstract 1327: Role of intra-tumoral bacteria in EGFR-tyrosine kinase inhibitor resistance
Authors: Li Wendong , Rotter-Maskowitz Aviva , Sun Ting , Zhang Keqiang , Straussman Ravid , Raz Dan
Published: July 2021

Mutations of the epidermal growth factor receptor (EGFR) are the most common group of actionable mutations in lung cancer, and they predict response to EGFR-tyrosine kinase inhibitos (EGFR-TKIs). The third-generation EGFR-TKI osimertinib is the standard of care for first-line treatment of patients with advanced EGFR-mutated lung cancer. Although most lung cancers with EGFR-mutation respond to osimertinib, resistance is eventually observed in all patients, and there are no approved targeted therapies once resistance to osimertinib occurs. Mechanisms of resistance to osimertinib are poorly understood and involve both EGFR and non-EGFR related pathways. Intra-tumoral bacteria are emerging as a cause of therapy resistance in cancer.Intra-tumoral bacteria have been reported in many cancers and emerging evidence suggests that the tumor microbiome plays an important role in drug resistance in a variety of cancers. But the link between intra-tumoral bacteria and therapy resistance in lung cancer remains elusive. We previously described the tumor microbiome identified within a cohort of non-small cell lung cancers. In order to determine if intra-tumoral bacteria within lung adenocarcinoma patient with EGFR mutation could play role on the resistance to EGFR-TKIs, such as osimertinib and erlotinib, we used a bacterial pre-conditioned medium (PCM) screening system which utilized various bacteria identified in lung cancer specimens. We used a cell viability evaluation method in GFP-labeled PC9 cells (EGFR Ex19del) to identify the bacterial PCM that may lead to resistance to EGFR-TKIs. We found that PCM from Chryseobacterium indologenes (C-PCM) markedly rescued PC9 cells from osimertinib or erlotinib treatment. We also found that proteinase K treatment eliminated the rescue of C-PCM on EGFR-TKI treatment, suggesting that a proteins within C-PCM are responsible for its effect of EGFR-TKI treatment. Mass spectrometry (MS) analysis showed that C-PCM does not degrade osimertinib or erlotinib, suggesting that C-PCM mediated resistance does not occur through drug degradation. Western blot analysis showed that C-PCM does not affect EGFR, phospho-EGFR, or AKT expression level but C-PCM significantly increased AKT phosphorylation level. Our current studies indicated that intra-tumoral bacteria within lung adenocarcinoma patient may leads to resistance to osimertinib and erlotinib. Further mechanistic studies of C-PCM mediated resistance are under way and may lead to new therapies to overcome osimertinib-resistance.

Citation Format: Wendong Li, Aviva Rotter-Maskowitz, Ting Sun, Keqiang Zhang, Ravid Straussman, Dan Raz. Role of intra-tumoral bacteria in EGFR-tyrosine kinase inhibitor resistance [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 1327.
Abstract 1348: Targeted degradation of PARP14 Using a heterobifunctional small molecule
Authors: Wigle Tim , Ren Yue , Molina Jennifer , Blackwell Danielle , Schenkel Laurie , Swinger Kerren , Cheug Anne , Abo Ryan , Minissale Elena , Lu Alvin , Majer Christina , Church William , Dorsey Bryan , Niepel Mario , Perl Nicholas , Kuplast-Barr Kristy , McEachern Kristen , Vasbinder Melissa , Keilhack Heike , Kuntz Kevin
Published: July 2021

PARP14 is an interferon-stimulated gene that is overexpressed in multiple tumor types and has been shown to promote the pro-tumor M2 polarization of macrophages and support Th2/Th17 signaling in models of allergic airway disease. PARP14 is a large 203 kDa protein that possesses a catalytic domain responsible for the transfer of mono-ADP-ribose to its substrates, three macrodomains that bind mono-ADP-ribose, a WWE domain that serves as a binding module for poly-ADP-ribose, and an RNA recognition motif. We have previously shown that the potent and reversible enzymatic inhibitor, RBN012759 (IC50 < 0.003 μM, 300-fold selective over monoPARPs, > 1,000-fold selective over polyPARPs), links PARP14 catalytic inhibition with suppression of the antitumor immune response in human primary macrophages and human kidney cancer explants. While this catalytic inhibitor of PARP14 was able to suppress IL-4-driven pro-tumor gene expression in macrophages, it is unknown what roles the non-enzymatic biomolecular recognition motifs play in the biological function of PARP14. To further understand this, we describe a heterobifunctional small molecule, RBN012811, based on a catalytic inhibitor of PARP14 that binds in the enzyme's NAD+-binding site and recruits the E3 ligase cereblon to ubiquitinate PARP14 and selectively target it for degradation. RBN012811 has a IC50 of 0.01 μM against PARP14 in a biophysical assay and is at least 200-fold selective over all other PARPs. In KYSE-270 cancer cells, RBN012811 has a half-maximal degradation concentration (DC50) of 0.005 μM and it does not cause degradation of other PARP enzymes. In human primary macrophages PARP14 degradation by RBN012811 led to a dose-dependent decrease of IL-10 release induced by IL-4 stimulation. Our data demonstrates that RBN012811 is a useful tool to enable further exploration of the role of PARP14 in inflammation and cancer.

Citation Format: Tim Wigle, Yue Ren, Jennifer Molina, Danielle Blackwell, Laurie Schenkel, Kerren Swinger, Anne Cheug, Ryan Abo, Elena Minissale, Alvin Lu, Christina Majer, William Church, Bryan Dorsey, Mario Niepel, Nicholas Perl, Kristy Kuplast-Barr, Kristen McEachern, Melissa Vasbinder, Heike Keilhack, Kevin Kuntz. Targeted degradation of PARP14 Using a heterobifunctional small molecule [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 1348.
Abstract 1368: Population pharmacokinetic-pharmacodynamic analysis of KHK2455 in patients with locally advanced or metastatic solid tumors
Authors: Mehta Krina , Koshiba Shoko , Hasegawa Maki , Tayama Tomonori , Marsteller Douglas , Fox Floyd , Liu Yi , Efuni Sergey , Healy Denis , Hruska Matthew
Published: July 2021

BACKGROUND: KHK2455 is an oral selective inhibitor of Indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an active immunotherapy to treat advanced or metastatic solid tumors. IDO1 is a rate-limiting enzyme that converts tryptophan (TRP) to kynurenine (KYN) and is linked to immunosuppression. IDO1 inhibition results in immune modulatory effects which may be important in boosting anti-cancer immune responses. The goal of this analysis was to develop a population pharmacokinetics (PK)-pharmacodynamics (PD) model to characterize KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors.

METHOD: Plasma KHK2455 concentration, plasma KYN and TRP concentration were obtained from 36 subjects with locally advanced or metastatic solid tumors who received KHK2455 at 0.3, 1, 3, 10, 30, or 100 mg QD as a monotherapy run-in followed by combination therapy with anti-CCR4 antibody mogamulizumab in this first in human study of KHK2455. The nonlinear mixed effects modeling approach was used to develop a population PK-PD model using the data from both mono- and combination-therapy. The ratio of KYN to TRP (K:T ratio) was used as a PD marker.

RESULTS: The population PK model included one-compartment model with transit compartment absorption, enterohepatic cycling, and linear elimination. The K:T ratio was well described by an indirect response model. Steady state simulations showed that, when compared to baseline, the K:T ratio decreased with increasing KHK2455 dose and reached to a constant nadir at 100 mg dose.

CONCLUSIONS: A population PK-PD model was established to characterize the KHK2455 exposure and its relationship to response in patients with locally advanced or metastatic solid tumors. The PK-PD model will enable dose optimization simulations for the planned studies.

ACKNOWLEDGEMENTS: We would like to express special appreciation to Dr. Solmaz Sahebjam, MD, for help in publishing this abstract.

Citation Format: Krina Mehta, Shoko Koshiba, Maki Hasegawa, Tomonori Tayama, Douglas Marsteller, Floyd Fox, Yi Liu, Sergey Efuni, Denis Healy, Matthew Hruska. Population pharmacokinetic-pharmacodynamic analysis of KHK2455 in patients with locally advanced or metastatic solid 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 1368.
Abstract 1375: Activity of pemetrexed in patients with driver oncogene positive non-small cell lung cancer and squamous histology
Authors: Nie Yunan , Patil Tejas , Camidge David Ross
Published: July 2021

Pemetrexed, a multi-targeted antifolate chemotherapy agent, has been used both as a single agent chemotherapy as well as in combination given its favorable side effect profile, and has been the only effective continuation maintenance chemotherapy regimen after initial doublet use associated with increased overall survival (OS) among non-squamous non-small cell lung cancers. The current labelled indications for pemetrexed in NSCLC are restricted to those with non-squamous histology due to previous studies that showed worse outcomes in patients with squamous histology when compared to non-squamous histology. More recently, however, in the era of increased molecular profiling of NSCLC, it has been observed that patients with ALK, ROS1, and RET gene fusions have demonstrated marked sensitivity to pemetrexed. This retrospective case series, therefore, evaluated the response to pemetrexed among a cohort of 9 oncogene-driven patients with squamous (or adenosquamous) histologies who did receive pemetrexed based chemotherapy. Response rates, progression free survival (PFS), and OS for these patients were compared to a historical group of patients published in previous studies that examined pemetrexed response. The results indicated a positive response to pemetrexed in patients with an actionable driver oncogene occurring in the context of squamous or adenosquamous histology. Patients in the oncogene-driven adenosquamous/squamous group had significantly higher response rates as compared to the historical squamous cell group and no significant difference in response rates as compared to the historical adenocarcinoma comparison group. In summary, contrary to prior studies, this case series does suggest that pemetrexed may be a viable treatment option in patients with squamous cell histology who also have a targetable mutation.

Citation Format: Yunan Nie, Tejas Patil, David Ross Camidge. Activity of pemetrexed in patients with driver oncogene positive non-small cell lung cancer and squamous histology [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 1375.
Abstract 1387: MET inhibition radiosensitizes KRAS-mutant rectal cancer
Authors: D'Ambrosio Antonio , Verginelli Federica , Orzan Francesca , Albano Raffaella , Casanova Elena , Luraghi Paolo , De Bacco Francesca , Bertotti Andrea , Trusolino Livio , Senetta Rebecca , Sapino Anna , Mastro Elena Del , Gatti Marco , Comoglio Paolo M. , Boccaccio Carla
Published: July 2021

Rectal carcinoma, representing about a third of all newly diagnosed colorectal cancers, is one of the most common malignant tumors. The standard of care for locally advanced rectal cancer (LARC), consisting of neoadjuvant chemo/radiotherapy prior to surgical resection, is poorly effective, leading to complete tumor regression only in 10-30% of the cases. Approximately 40% of LARC harbor activating KRAS mutations, which have been extensively associated with primary resistance to targeted EGFR therapy and with radioresistance as well. Previous work showed that the MET receptor tyrosine kinase supports radioresistance and can be inhibited to radiosensitize tumor cell subpopulations retaining stem-like properties. Here, we show that LARC often express high levels of MET and can be successfully radiosensitized by MET inhibition. This was assessed in rectal stem-like cells isolated from human tumors (rectospheres), and transplanted in the mouse to regenerate tumors that faithfully reproduce the phenotype, the genotype and the therapeutic response of the original tumor. Mechanistically, we found that radioresistant KRAS-mutant rectospheres display significantly higher basal levels of RAD51, a master regulator of DNA homologous recombination repair, and increased RAD51 recruitment to irradiation-induced DNA double-strand breaks, as compared with KRAS-wild type rectospheres. Importantly, we showed that MET pharmacological inhibition by small-molecule kinase inhibitors, combined with radiotherapy, impairs RAD51 expression and function. This leads to DNA damage accumulation and results in effective radiosensitization of K-RAS-mutant rectal stem-like cells in vitro and in vivo, and significant inhibition of experimental tumors. Therefore, preclinical evidence is provided that MET can be exploited as a therapeutic target to radiosensitize KRAS-mutant rectal cancer at stem-like cell level.

Citation Format: Antonio D'Ambrosio, Federica Verginelli, Francesca Orzan, Raffaella Albano, Elena Casanova, Paolo Luraghi, Francesca De Bacco, Andrea Bertotti, Livio Trusolino, Rebecca Senetta, Anna Sapino, Elena Del Mastro, Marco Gatti, Paolo M. Comoglio, Carla Boccaccio. MET inhibition radiosensitizes KRAS-mutant rectal 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 1387.
Abstract 1430: In vivo PoC study and design for Phase I clinical study of SJP1604, a nucleolin-targeted therapeutic agent to treat entire population of relapsed/refractory acute myeloid leukemia patients
Authors: Um Jihyun , Lee Dohyeong , Kim So Hee , Huh Eun-Hye , Park Yongbin , Moon Sung Hwan , Lee Soo Jin , Lee Je-Hwan , Ki Min-Hyo
Published: July 2021

SJP1604 (APTA-16) is an aptamer-drug conjugate (APTA-DC) specifically targeting nucleolin, which is highly expressed only on the cell membrane of acute myeloid leukemia (AML) cells including relapsed/refractory aute myeloid leukemia (R/R AML). We previously presented the outstanding anti-leukemic activity of SJP1604 on AML cells including drug-resistant AML cells while standard chemotherapies showed no efficacy in vitro and in vivo. Therefore, we were able to conclude that only SJP1604 exhibits excellent resistance overcoming efficacy regardless of genetic defects of AML cells. Additionally, we recently identified that SJP1604 markedly eradicated AML cell engraftment with decreasing expression level of nucleolin protein in the bone marrow cells of MOLM-13 xenograft mouse model. These findings demonstrate that SJP1604 contributes to anti-leukemic effects through the regulation of nucleolin protein. We also figured out that nucleolin as a clinical biomarker was significantly highly expressed on AML and R/R AML patient-derived bone marrow cells. In particular, nucleolin expression is highly overexpressed in the bone marrow cells of entire population of R/R AML patients. Upto recent, considered as one of the major targeted therapeutics for AML, FLT3 inhibitors can target 25-30% of AML patients only. Therefore, our results mentioned above are very noteworthy finding showing the high potential of SJP1604 to be further developed as the first innovative targeted therapy to treat entire population of R/R AML patients. Herein, we show a phase I clinical trial design of SJP1604 to perform an open-label, first-in-human, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity in patients with R/R AML.

Citation Format: Jihyun Um, Dohyeong Lee, So Hee Kim, Eun-Hye Huh, Yongbin Park, Sung Hwan Moon, Soo Jin Lee, Je-Hwan Lee, Min-Hyo Ki. In vivo PoC study and design for Phase I clinical study of SJP1604, a nucleolin-targeted therapeutic agent to treat entire population of relapsed/refractory acute myeloid leukemia patients [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 1430.
Abstract 1431: Role of emt biomarkers in mediating osimertinib resistance in non-small cell lung cancer
Authors: Racherla Kavya Sri , Dovalovsky Katrina , Puri Neelu
Published: July 2021

Osimeritinib (OR), a Tyrosine Kinase Inhibitor is a first-line therapy in EGFR-mutant NSCLC patients. Resistance to OR treatment may occur due to acquired C797S mutations, MET amplifications and ALK rearrangements and other mechanisms not clearly defined. EMT may be one of the reasons for TKI resistance. EMT is a process by which epithelial cells acquire mesenchymal characteristics that increase invasiveness. We hypothesize that loss of E-cadherin during EMT, results in abnormal localization of p120 catenin, an E-cadherin regulating protein, and Kaiso factor, a repressor of Wnt signaling, promoting oncogenesis. Protein arginine methyl transferase 1 (PRMT1) an EMT regulator catalyzes methylation of Twist1, which represses E-cadherin. However, their role in OR resistance is still unknown. We have made parental (P) NSCLC cells, H2170, H358, H1975 and H3255 resistant to OR. MTT assays were performed on the parental cells and OR resistant cells which showed that the H2170OR, H3255OR, H358OR, H1975OR cells had IC50 for OR, 2.8-14 fold higher in comparison to parental cells, respectively. We further performed qPCR to study the modulation of EMT biomarkers in OR cells as compared to parental cells and found upregulation of PRMT1, p120 catenin and Kaiso factor by 1.5-3.67 fold respectively in H1975 cells and 1.5-5.73 fold in H3255 cells. Immunofluorescence studies in H1975OR cells for expression of PRMT1 showed that there was 3.18 fold increase as compared to 2.21 fold increase in Erlotinib resistant H1975 (H1975ER) and 4.77 fold increase in H3255OR as compared to 2.27 fold increase in H3255ER. After transfection with p120 siRNA we found that OR efficacy was increased by 33% in comparison to mock siRNA and OR treated cells. The percentage wound closure after 24 hours was found to be 26.2% in the p120-catenin siRNA transfected cells as compared to 7.4%.in mock siRNA transfected cells (p<0.05) indicating its role in EMT and cell migration. Furthermore, our results showed increased expression of p120 catenin in smokers with 50% of smokers showing high expression compared to 0% and 5.8% of quit smokers and nonsmokers indicating that high p-120 expression was associated with smoking (P=0.002). In conclusion, biomarkers like PRMT1 may mediate the process of EMT by methylation of Twist1 and upregulation of p120 that prevents transcriptional repression of Kaiso factor target genes, promoting EMT in OR and ER resistant cells. p-120 expression was found to be higher in smokers compared to quit/nonsmokers indicating that it may have a potential role in lung cancer.

Citation Format: Kavya Sri Racherla, Katrina Dovalovsky, Neelu Puri. Role of emt biomarkers in mediating osimertinib resistance 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 1431.
Abstract 1443: CHKing melanoma: CHK1 inhibitor +low dose hydroxyurea triggers immunogenic cell death and immunostimulatory cytokine expression to drive an anti-tumor immune response
Authors: Gabrielli Brian G. , Proctor Martina , Cruz Jazmina Gonzalez , Zeng Bijun , Dolcetti Riccardo , Keane Colm , Haass Nikolas , Wells James
Published: July 2021

About half of melanomas respond to immunotherapy, but we currently lack reliable markers to identify likely responders. Therefore, a large number of patients receive this expensive therapy for no benefit. We have previously shown that inhibition of the cell cycle regulator, Checkpoint kinase 1 (CHK1), with subclinical dose of the replication stress inducer hydroxyurea is cytotoxic in a high proportion of melanomas tested. We now report that CHK1 inhibitor + low dose hydroxyurea (LDHU) treatment triggers immunostimulatory cytokine and chemokine expression, and an immunogenic form of cell death. In xenograft models, the drug combination blocks tumor growth for extended periods after the completion of treatment. In syngeneic mouse melanoma models, the drug combination also effectively controls tumor growth and induces regression in a proportion of cases. It also increases immune cell infiltration and activation of a tumor directed cytotoxic T cell response. We also demonstrate that the drug combination does not adversely affect an adaptive immune response or rapidly proliferating human T cells. The mechanism by which drug treatment promotes cytokine expression is unlikely to involve the cGAS-STING signalling pathway which is commonly defective in melanomas. Using two engineered mouse melanoma models we have found that CHK1 inhibitor + LDHU increases cytotoxic CD8+ T cells and NK cell infiltration and activation, but we have also found increased CD4+ Treg tumor infiltration and increased CD8+ T cell PD-1 expression. We have also found increased expression of other immune checkpoint regulators. This indicates a strong anti-tumor immune response is initiated but immune suppression and T cell exhaustion have limited the extent of the response of the tumor infiltrating T cells. However, circulating T cells retained strong anti-tumor activity. The harvested tumors from the drug combination treated mice that do increase in size after treatment show strong evidence of cytotoxic activity. These data provide evidence that CHK1 inhibitors + LDHU is well tolerated and triggers a strong anti-cancer immune response that should combine with immune therapy, although the selection of the target of the immunotherapy will be critical for successfully overcoming the immune suppression triggered.

Citation Format: Brian G. Gabrielli, Martina Proctor, Jazmina Gonzalez Cruz, Bijun Zeng, Riccardo Dolcetti, Colm Keane, Nikolas Haass, James Wells. CHKing melanoma: CHK1 inhibitor +low dose hydroxyurea triggers immunogenic cell death and immunostimulatory cytokine expression to drive an anti-tumor immune response [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 1443.
Abstract 1457: Discovery of biomarkers assocaited with treatment responses to sorafenib and transarterial chemoembolisation (TACE) in Chinese hepatocellular carcinoma patients
Authors: Wu Zhiqiang , Zhou Xiaoyu , Wang Shengzhou , Li Jinhuai , Liu Jun , Guo Wenbo
Published: July 2021

Background: Liver cancer is one of the most deadly tumors. Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers. Sorafenib, a multi-target kinase inhibitor, is one the main systemic therapy drug of HCC. It increased the median overall survival time from 7.9 mo to 10.7 mo for patients with advanced stage HCC. However, about 60% of HCC patients done't respond well to sorafenib, and most of them develop progression in below 6 mo. Similarly, TACE is also an effective treatment of HCC but only with partial response rate. Therefore, finding new strategies to screen the best matched patients is key to improve the efficacy of sorafenib and TACE treatment.

Methods: We evaluated the efficacy of sorafenib starting with 98 HCC patients but only 73 patients completed the study because 24 dropped out due to death (n=2), drug violation (n=4), adverse reactions (n=3), and failure of outcome evaluation (n=15). Forty-five patients were treated by TACE. We divided the patients to a progressive disease (PD) group (46.6%, 34 patients) and a Non-PD group (53.4%, including 2 with partial response and 37 with stable disease) based on their CT and MRI evaluations. At the same time, we performed Whole-exome sequencing (WES) on the tumor samples and patient-matched blood samples.

Results: We found the PD group, comparing with the Non-PD group, had a higher proportion of patients with MSI (P = 0.028) and mutations in WNT/ß-catenin signaling and chromatin modification pathways, as well as cytoband deletions at 21q11, 1p21.1, 8q24.3, 11p11.12, 5p15.33, and 17q25.3. On contrast, cytoband amplifications at 12p13, 21q22.3, and 8q21 only appeared in the Non-PD group. We also observed a prominent decrease in the PD group COSMIC mutational signature 10 which is believed to associate with POLE mutation. We found MUC16 and FLG2 genes were related to a better survival time. Mutation of NANOGNB, and cytoband deletions at 3q11.2, 4q13.2,11q11,11q22.2 and 17q25.3 were related to a shorter survival time. (p<0.05 for all above except otherwise specified).

Conclusions: We found several genes and chromosome variation were associated with sorafenib efficacy and overall survival in HCC patients. These findings indicated that mutations and chromosomal fragment deletions can lead to sorafenib resistance. Mutations of MUC16 and FLG2 may be potential drug targets in HCC.

Citation Format: Zhiqiang Wu, Xiaoyu Zhou, Shengzhou Wang, Jinhuai Li, Jun Liu, Wenbo Guo. Discovery of biomarkers assocaited with treatment responses to sorafenib and transarterial chemoembolisation (TACE) in Chinese hepatocellular carcinoma patients [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 1457.
Abstract 1459: PTP4A3 phosphatase is a novel drug target for epithelial ovarian cancer
Authors: Cornelison John Robert , Rastelli Ettore J. , Hart Duncan J. , Mendelson Anna J. , Sharlow Elizabeth R. , Wipf Peter , Lazo John S.
Published: July 2021

High grade serous ovarian cancer (HGSOC) is the deadliest epithelial ovarian cancer (EOC) variant, with a bleak outcome that kills >14,000 women annually in the US. In past four decades, first line therapies have changed only modestly. While dramatic advances in targeted- and immune-based therapies have been seen in some solid tumors, they have not been reported in patients with HGSOC. Recurrent and chemoresistant HGSOC is common. Therefore, it is imperative that new HGSOC drug targets be interrogated. The Protein Tyrosine Phosphatases of Regenerating Liver (PRL or PTP4A) family is significantly upregulated in a variety of tumors, including HGSOC. A bioinformatic analysis of the ovarian cancer using the KMplot Survival Database revealed that high PTP4A3 expression was associated with poor survival in EOC (p<0.0001, hazard ratio (HR)=1.35). In HGSOC early stage disease, PTP4A3 expression levels were also correlated with survival (stage I/II- p=0.0013, HR=3.2), with low expressing patients surviving twice as long as high expressing patients (upper quartile survival in low expression cohort = 81.2 months compared to high expression cohort = 44.3 months). This survival difference appeared independent of myc amplification and was more pronounced in advanced disease (stage III/IV). qPCR profiling of established HGSOC cell lines, including Kuramochi, COV362 and OVCAR4, showed 5-20 fold increases in PTP4A3 gene expression versus nonmalignant control cells. A potent, specific, allosteric small molecule inhibitor of PTP4A3, KVX-053, markedly reduced the growth and survival of chemoresistant and chemosensitive EOC cell lines independent of their BRCA or p53 status. Moreover, treatment of the HGSOC OVCAR4 cell line with KVX-053 (1 μM) inhibited the oncogenic Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway through loss of phosphorylation of STAT3. Evaluation of a series of next-generation KVX-053-based analogs including chemodegraders yielded chemotypes with enhanced cytotoxic effects. These results demonstrate a clear path for the development of the PTP4A family of tyrosine phosphatases as a novel therapeutic target in a HGSOC.

Citation Format: John Robert Cornelison, Ettore J. Rastelli, Duncan J. Hart, Anna J. Mendelson, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. PTP4A3 phosphatase is a novel drug target for epithelial ovarian 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 1459.
Abstract 1479: Pan-cancer efficacy of BRAF and/or MEK inhibitors in BRAF V600-mutant multiple non-melanoma cancers: A clinico-genomic study
Authors: Adashek Jacob J. , Desai Aakash P. , Menta Arjun K. , Roszik Jason , Subbiah Vivek
Published: July 2021

Background: BRAF and MEK inhibitors are currently FDA approved for melanoma, non-small cell lung cancer, and anaplastic thyroid cancer. The lack of clinical benefit with BRAF inhibition in BRAF V600+ colorectal cancer (CRC) has prevented its tissue-agnostic drug development. However, updated results from Vemurafenib-Basket study (Cancer Discov. 2020 May;10(5):657-663 ) and the NCI-match trial ( J Clin Oncol. 2020 Nov 20;38(33):3895-3904) reveal that BRAF pathway inhibition is active in > 20 unique cancer types.

Objective: We aimed to describe the characteristics of BRAF V600 and study real-world outcomes using a clinico-genomic analysis using the AACR Genie database and the current medical literature.

Methods: We reviewed the AACR GENIE database for the prevalence of BRAF V600 mutations across tumor types. We conducted a literature search (using PubMed from 2012-2019) for case reports of clinical response and outcomes in patients with BRAF V600 mutation-positive non-melanoma cancers who received BRAF inhibitor therapy.

Results: Among 96,324 samples, BRAF V600 mutations were seen in 43 different tumor types across 2,963 samples (3.07 %) in the AACR GENIE database. BRAF V600 was most commonly present in thyroid cancer (40.9%), parathyroid cancer (31.8%), melanoma (26.1%), histiocytosis (25.7%), and head and neck NOS (14.3%). Literature review revealed total of 178 cases across 69 tumor types. The most common cases included Erdheim-Chester disease (n = 30, 16.9%), papillary thyroid carcinoma (n=16, 8.9%), anaplastic thyroid carcinoma (n = 13, 7.3%), and hairy cell leukemia (n = 13, 7.3%). Furthermore, dabrafenib (BRAF), dabrafenib/trametinib (BRAF+MEK), trametinib(MEK), vemurafenib (BRAF), vemurafenib/trametinib (BRAF+MEK), vemurafenib/cobimetinib (BRAF+MEK) were used in 34% (n =56), 16% (n = 27), 4% (n = 6), 44% (n = 72), 1% (n = 1), 2% (n =3), respectively. Overall, median PFS was 6.5 months, and median OS was 28.5 months with a median duration of response (DOR) of 8 months.

Conclusion: BRAF V600 mutations are prevalent across multiple non-melanoma cancers, lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers. Continued drug development is warranted beyond the current BRAF+/- MEK approved cancers.

Citation Format: Jacob J. Adashek, Aakash P. Desai, Arjun K. Menta, Jason Roszik, Vivek Subbiah. Pan-cancer efficacy of BRAF and/or MEK inhibitors in BRAF V600-mutant multiple non-melanoma cancers: A clinico-genomic study [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 1479.
Abstract 1488: Viral molecular mimicry influences the antitumor immune response in murine and human melanoma
Authors: Chiaro Jacopo , Kasanen Henna , Whalley Thomas , Capasso Cristian , Feola Sara , Grönholm Mikaela , Hamdan Firas , Peltonen Karita , Hernberg Micaela , Mäkelä Siru , Karhapää Hanna , Brown Paul , Martins Beatriz , Fusciello Manlio , Ylösmäki Erkko , Kreutzman Anna , Mustjoki Satu , Szomolay Barbara , Cerullo Vincenzo
Published: July 2021

Molecular mimicry is known to be one of the leading mechanisms by which infectious agents may induce autoimmunity. However, whether a similar mechanism triggers anti-tumor immune response is unexplored, and the role of anti-viral T-cells infiltrating the tumor has remained anecdotal. To address this question, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we showed that, in mice, viral pre-existing immunity enhanced the efficacy of cancer immunotherapy via molecular mimicry. Specifically, when treated with a cancer vaccine consisting of peptides with a high degree of homology with specific viral peptides, the mice with induced pre-existing immunity to these viral peptides showed significantly better anti-tumor response.To understand whether this mechanism could partly explain immunotherapy-response in humans, we analyzed a cohort of melanoma patients undergoing PD1 treatment with high IgG titer for Cytomegalovirus (CMV). In this cohort of patients, we showed that high level of CMV-antibodies was associated with a prolonged progression free survival, and found that in some cases PBMCs could cross-react with both melanoma and CMV homologous peptides. Finally, T-cell TCR sequencing revealed expansion of the same CD8+ T-cell clones, when PBMCs were pulsed with tumor- or homologous viral peptides.In conclusion, we have demonstrated that pre-existing immunity and molecular mimicry could explain part of the response observed in immunotherapy. Most importantly, we have developed a tool able to identify tumor antigens and neoantigens based on their similarity to pathogen antigens, in order to exploit molecular mimicry and cross-reactive T-cells in cancer vaccine development.

Citation Format: Jacopo Chiaro, Henna Kasanen, Thomas Whalley, Cristian Capasso, Sara Feola, Mikaela Grönholm, Firas Hamdan, Karita Peltonen, Micaela Hernberg, Siru Mäkelä, Hanna Karhapää, Paul Brown, Beatriz Martins, Manlio Fusciello, Erkko Ylösmäki, Anna Kreutzman, Satu Mustjoki, Barbara Szomolay, Vincenzo Cerullo. Viral molecular mimicry influences the antitumor immune response in murine and human melanoma [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 1488.
Abstract 1494: IgE receptor-activated human mast cells have potent anti-cancer properties
Authors: Kepley Chris , Ferrydouni Mohammad , Motaghed Mona , Dellinger Kristen
Published: July 2021

The purpose of this study was to test the hypothesis that human mast cells (MC) have anti-tumor mediators that can be targeted to tumor specific antigens, induced to release these mediators, and cause cancer cell apoptosis. Breast cancer (BC) continues to be a significant cause of mortality for women in the United States. The oncogene HER2/neu is overexpressed in BC and is validated target for cancer therapeutics. New immunotherapy strategies and combinations of immune agents with non-redundant mechanisms of action are needed. The role of human tissue mast cells (MC) in the pathology of many cancers is not known. Nonetheless, high densities of MC are associated with favorable prognosis in certain types of cancer such as BC suggesting an anti-tumor effect. We previously reported that human adipose cells can be differentiated into autologous, fully functional MC (ADMC) capable of releasing mediators upon FcϵRI stimulation that induce BC cell death of cell suspensions of SK-BR3. Further data is presented demonstrating the anti-tumor effects of ADMC using BC tumor masses. The ADMC, sensitized with breast cancer-specific IgE anti-HER2/neu, bound to and were activated by, HER2/neu-positive human BC cells. The anti-HER2/neu IgE-sensitized ADMC bound to, infiltrated, and induced apoptosis of HER2/neu-positive BT-474 BC tumor masses as determined by time-lapse, live cell confocal imaging. Specific, HER2/neu IgE-mediated binding was also verified in vivo using immunocompromised xenograft models. Further studies are warranted to determine if tumor-targeted, autologous MC may be a new way to treat solid tumors.

Citation Format: Chris Kepley, Mohammad Ferrydouni, Mona Motaghed, Kristen Dellinger. IgE receptor-activated human mast cells have potent anti-cancer properties [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 1494.
Abstract 1498: Nanobody-based CAR T cells targeting B7-H3 in pancreatic cancer
Authors: Li Dan , Wang RuiXue , Liang Tianyuzhou , Croix Brad St. , Ho Mitchell
Published: July 2021

Pancreatic cancer is a common cause of cancer-related mortality worldwide with a poor 5-year survival rate. Adoptive transfer of T cells engineered with chimeric antigen receptors (CAR T cells) have shown promising potency in hematological malignancies, but it is more challenging to apply CAR T cells in the treatment of solid tumors. One of the major barriers is the lack of appropriate therapeutic targets. B7-H3 (CD276) is an emerging and promising pan-cancer target that is overexpressed in multiple solid tumors including pancreatic ductal adenocarcinoma (PDAC) and neuroblastoma (NB) but limited in normal tissues. Interestingly, it is highly expressed in not only tumor cells but also tumor-associated myeloid cells in the tumor microenvironment. In this study, we isolated a panel of novel B7-H3 specific nanobodies from our camel VHH single domain phage libraries. These nanobodies bind to human B7-H3-expressing tumor cell lines and cross-react with B7-H3 of different species. Notably, three nanobody-based CAR T cells (B12, C4 and G8) demonstrate potent cytolytic effects on B7-H3 positive PDAC and NB cell lines in vitro. In particular, CAR T cells have been tested in a metastatic PDAC model and a NB model in mice, showing that C4 and B12 nanobody-based CAR T cells have potent antitumor efficacy without evident side effects. Therefore, we conclude that our new B7-H3 targeted nanobody-based CAR T cells, in particular C4 and B12 derived CAR T cells, are promising for treating solid tumors such as pancreatic cancer and other deadly solid tumors.

Citation Format: Dan Li, RuiXue Wang, Tianyuzhou Liang, Brad St. Croix, Mitchell Ho. Nanobody-based CAR T cells targeting B7-H3 in pancreatic 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 1498.
Abstract 1502: Pre-conditioning modifies the tumor microenvironment to enhance solid tumor CAR T cell efficacy and endogenous immunity
Authors: Murad John P. , Tilakawardane Dileshni , Park Anthony K. , Kennewick Kelly T. , Lopez Lupita S. , Lee Hee J. , Gittins Brenna J. , Chang Wen-Chung , Tran Chau P. , Martinez Catalina , Wu Anna M. , Reiter Robert E. , Dorff Tanya B. , Forman Stephen J. , Priceman Saul J.
Published: July 2021

Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its utility in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate cancer are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human prostate stem cell antigen knock-in (hPSCA-KI) immunocompetent mouse model and syngeneic murine PSCA CAR T cells, we performed analyses of normal and tumor tissues by flow cytometry, immunohistochemistry, and/or RNA sequencing. We further assessed the beneficial impact of cyclophosphamide (Cy) pre-conditioning on modifications to the immunosuppressive TME and impact on PSCA-CAR T cell safety and efficacy. We observed an in vivo requirement of Cy pre-conditioning in uncovering the efficacy of PSCA-CAR T cells in prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous PSCA expression. This combination also dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, and endogenous as well as adoptively-transferred CAR T cells, resulting in long-term anti-tumor immunity.

Citation Format: John P. Murad, Dileshni Tilakawardane, Anthony K. Park, Kelly T. Kennewick, Lupita S. Lopez, Hee J. Lee, Brenna J. Gittins, Wen-Chung Chang, Chau P. Tran, Catalina Martinez, Anna M. Wu, Robert E. Reiter, Tanya B. Dorff, Stephen J. Forman, Saul J. Priceman. Pre-conditioning modifies the tumor microenvironment to enhance solid tumor CAR T cell efficacy and endogenous immunity [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 1502.
Abstract 1526: Single-step precision genome engineering platform enables versatile generation of personalized (neoTCR) adoptive cell therapy T cells with supplementary anti-tumor attributes
Authors: Dubreuil Michael M. , Tran Charles W. , Purandare Bhamini , Lu William , Byers James , Mass Michal , Jacoby Kyle , Sennino Barbara , Franzusoff Alex , Mandl Stefanie J.
Published: July 2021

Personalized autologous TCR-T cell therapies targeting neoE-specific neoepitopes (NeoE) derived from tumor-exclusive mutations are a compelling approach for the treatment of patients with solid tumors. Using the ultra-sensitive imPACT Isolation Technology®, antigen-experienced neoE-specific CD8 T cells are captured from the blood of patients with solid cancers followed by cloning of the cognate neoepitope-specific HLA class I-restricted T cell receptors (HLA-I neoTCRs). Using DNA-mediated (non-viral) precision genome engineering technology, fresh CD8 and CD4 T cells from the same patient with cancer are engineered to express the HLA-I neoTCR. We have further innovated this platform of precision genome engineering to confer neoTCR-T cells with supplementary gene edits to address the array of potential sources for tumor immune evasion. Two examples of the versatility of this single step gene editing platform are described in this study: 1) concurrent expression of a CD8 co-receptor (CD8coR) to augment activity of CD4 T cells engineered with lower affinity HLA-I neoTCRs; and 2) simultaneous disruption of TET2 expression in T cells, which has previously been reported to positively affect T cell differentiation and persistence. The data shows that these simultaneous supplemental gene modifications were achieved with high efficiency, resulting in fully functional CD8 and CD4 neoTCR-T cells. Surface expression of CD8coR together with the neoE-targeted TCR increased T cell effector function and antigen-specific tumor cell killing. NeoTCR-T cells with concomitant deletion of TET2-expression exhibited enhanced cytotoxicity against neoantigen-expressing tumor cells. Together, these results demonstrate the applicability of this versatile precision genome engineering platform technology to yield enhanced next generation neoTCR-T cell therapies to expand the potential for clinical benefit in treating persons with solid cancers.

Citation Format: Michael M. Dubreuil, Charles W. Tran, Bhamini Purandare, William Lu, James Byers, Michal Mass, Kyle Jacoby, Barbara Sennino, Alex Franzusoff, Stefanie J. Mandl. Single-step precision genome engineering platform enables versatile generation of personalized (neoTCR) adoptive cell therapy T cells with supplementary anti-tumor attributes [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 1526.