bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P086: Identification of pharmacodynamic and sensitivity biomarkers for TACH101, a pan-inhibitor of KDM4 histone lysine demethylase
Authors: Perabo Frank , Yoo Sanghee , Chandhasin Chandtip , Rosario Joselyn Del , Chen Young K. , Filvaroff Ellen , Stafford Jeffrey A. , Quake Stephen , Clarke Michael F. 
Published: December 2021

Abstract
Background: TACH101 is a novel, selective and potent inhibitor of KDM4 in development for advanced cancers. KDM4 plays a key role in epigenetic regulation by removing methyl marks on histone H3K9 and H3K36. Overexpression of KDM4 leads to dysregulation of transcription, cell cycle, and DNA replication/repair processes and has been associated with many cancer types. Methods: Candidate pharmacodynamic (PD) and sensitivity biomarkers for TACH101 were evaluated in vitro and in vivo using cancer cell lines, mouse xenograft models, gene microarrays, ChIP-seq, and ChIP-qPCR. Results: Evaluation of differential gene expression from tumor tissue identified several candidates as potential PD markers for TACH101 activity. In particular, direct binding of KDM4 to Protein Phosphatase 1 Regulatory subunit 10 (PPP1R10 or PNUTS) was confirmed by ChIP-seq in cell lines from esophageal (KYSE-150), breast (MDA-MB-231) and lymphoma (OCI-Ly19) cancers. TACH101 treatment caused 86% repression of PNUTS mRNA, as well as a 51% increase in H3K9me3, a mark of repressed transcription. A 78% decrease in H3K36me3 at the PNUTS gene was also observed. PNUTS as a target of KDM4 was validated via ChIP-qPCR in xenograft tumors of KYSE-150, OCI-Ly19 and SU-60 (colorectal). In vivo, maximum inhibition of PNUTS was reached at 8 hours post TACH101 administration, when TACH101 concentration was 100-200 nM in tumors. In addition, extensive bioinformatics analysis using &gt;300 cancer cell lines showed that cell lines with MSI-high (MSI-H) status tended to be more sensitive to TACH101 in vitro. This association was found with other markers of MSI-H status such as MMR gene mutations, MLH1 methylation status, and overall mutation frequency. To further test this association, TACH101 was evaluated in a panel of patient-derived xenograft (PDX) and organoid models. The results showed a strong correlation of TACH101 sensitivity with MSI-H status (IC50 ranges 1-150 nM). Conclusions: Candidate PD biomarkers of TACH101 activity for clinical evaluation have been identified and further studies are ongoing to explore current and additional markers. In addition, MSI-H status was associated with increased sensitivity to TACH101, which may be useful for enriching for select patient populations in clinical studies.
Citation Format: Frank Perabo, Sanghee Yoo, Chandtip Chandhasin, Joselyn Del Rosario, Young K. Chen, Ellen Filvaroff, Jeffrey A. Stafford, Stephen Quake, Michael F. Clarke. Identification of pharmacodynamic and sensitivity biomarkers for TACH101, a pan-inhibitor of KDM4 histone lysine demethylase [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P086.
Abstract P092: A novel approach to target drug-resistance in thyroid cancer by regulating Annexin 7 (ANXA7)/p21 axis
Authors: Radhakrishnan Surya , Bera Alakesh , Puthillathu Narayanan , Gana Nahbuma , Subramanian Madhan , Russ Eric , Paria Anubhuti , Paria Swarnarup , Rothwell Stephen , Pollard Harvey B. , Srivastava Meera 
Published: December 2021

Abstract
Thyroid cancer is the most common endocrine malignancy in the United States. The survival rate of thyroid cancer patients is high. However, there is a group of patients with poor prognosis due to the development of drug resistance. Differential expression and mutation of the BRAF, Met, and p53 genes have been correlated with the progression and aggressiveness of this cancer, and over 60% of thyroid cancer patients were found to have a V600E mutation in BRAF. ANXA7 is a multifunctional protein that has been found to act as a tumor suppressor in many cancers. In this study, we focused on the expression of ANXA7 in relation to the BRAF mutation and its functional role in regulating thyroid cancer progression, aggressiveness, and drug-sensitivity. High-throughput RNA-seq and protein array studies indicated a lower ANXA7 protein expression linked with thyroid cancer. Additionally, ANXA7 was found to be lower in the thyroid cancer cell lines with the BRAF mutation. To test ANXA7’s role in regulating drug-sensitivity, thyroid cancer cells were treated with different BRAF and MEK inhibitors. Both groups of inhibitor treatment on the thyroid cancer cells resulted in an increase in ANXA7 expression, a decrease in Ph-ERK, and an increase in apoptotic markers. We also found that the cyclin-dependent kinase inhibitor p21 is a novel regulator of BRAF mediated chemoresistance, and elevation of both p21 and ANXA7 through the combination of drugs resulted in a synergistic effect in the apoptotic pathway. Together, these results provide new insights into thyroid malignancy and its drug resistance mechanism involving the ANXA7/p21/BRAF/MAPK pathway. Future translational-based approaches with high-throughput functional screenings are necessary to develop a novel and effective ANXA7-based therapeutic strategy for thyroid cancer.
Citation Format: Surya Radhakrishnan, Alakesh Bera, Narayanan Puthillathu, Nahbuma Gana, Madhan Subramanian, Eric Russ, Anubhuti Paria, Swarnarup Paria, Stephen Rothwell, Harvey B. Pollard, Meera Srivastava. A novel approach to target drug-resistance in thyroid cancer by regulating Annexin 7 (ANXA7)/p21 axis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P092.
Abstract P094: Targeted sequencing revealed clonal genetic changes in spatially different foci in urothelial carcinoma of bladder
Authors: Ugurlu M. Talha , Goldberg Rachel , Sadhukhan Pritam , Hoque Mohammad O. 
Published: December 2021

Abstract
Urothelial Carcinoma of Bladder (UCB) is a disease of multiple origins of the same bladder with varying in morphology and genetic changes. The origin of spatially different tumors in the same bladder has been proposed to occur through clonal changes with intraluminal migration or field effect with synchronous transformation of multiple cells by carcinogens. A clear molecular understanding of the origin of multifocal UCB will have important implications for the proper tailoring of personalized targeted treatment and diagnostics. Despite efforts to identify intertumoral heterogeneity, the clonal origin of UCB is still debated. To further understand the genetic mechanism behind the multifocality of UCB, we performed targeted next-generation sequencing (tNGS) on 39 UCB lesions obtained from 15 cystectomized bladders. Germline distant muscle DNA was used as a control. We technically validated selected mutational events by using ultra-sensitive droplet digital PCR (ddPCR). Our data showed that multifocal UCB is of clonal origin, with lesions from individual patients displaying nearly identical mutational landscapes, with few heterogeneous events that may have been acquired at a later point. tNGS demonstrated similar genetic drivers within the same patient and reveal that clonal expansion is an early event of tumorigenesis. In addition, we found distinct gene mutations in different UCB patients suggesting prominent interpatient heterogeneity of clonal events in the UCB. Among others, our result showed that TP53, FGFR3, and NOTCH4 are the most frequently mutated genes in UCB samples. ddPCR assay of mutational events on TP53, FGFR3, AKT, PIK3CA genes confirmed TNGS data and solidified that mutation in TP53, FGFR3, AKT, PIK3CA genes are associated with tumorigenesis of uroepithelium. In summary, this study conveys insight into the clonal origin of multifocal UCB and demonstrates that TNGS is a sensitive and reliable method for interrogating the molecular landscape of UCB. These findings also may inform clinical practice as sequencing of a single focus from a patient presenting with the multifocal disease may be sufficient to understand the mutational profile and guide personalized treatment and risk stratification.
Citation Format: M. Talha Ugurlu, Rachel Goldberg, Pritam Sadhukhan, Mohammad O. Hoque. Targeted sequencing revealed clonal genetic changes in spatially different foci in urothelial carcinoma of bladder [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P094.
Abstract P106: Reprogramming regulatory T cells (Treg) using a MALT1 inhibitor for cancer therapy
Authors: Keller Peter , Mazo Irina , Gao Yun , Reddy Vijayapal , Caballero Francisco , Kazer Sam , Miller Dannah , Gianani Roberto , Marvin James E. , Stephens Bret , Beatty Gregory L. , von Andrian Ulrich H. , Mempel Thorsten R. 
Published: December 2021

Abstract
Background Despite transforming effects of immune checkpoint blockade (ICB) therapy, objective response rates are low for most solid tumors. In the tumor microenvironment (TME), regulatory T cells are functionally unstable, likely due to changes in Treg metabolism seen in the tumor milieu. Destabilized Treg are susceptible to reprogramming wherein they can be induced to lose their immunosuppressive function and to secrete interferon-gamma (IFN-g). Thus, Treg reprogramming offers a novel strategy to sensitize unresponsive tumors to ICB. Notably, blockade of MALT1 protease induces Treg reprogramming in the TME but without affecting Treg in healthy tissue. MPT-0118, an orally dosed MALT1 inhibitor, was developed to reprogram Treg in the TME and is currently being assessed in patients with advanced tumors. Approach Treatments included MPT-0118 and anti-PD-1. In vivo studies in mice assessed anti-tumor effects using D4M.3A, B16F10, and MC38 syngeneic tumors. Human and mouse tumor tissues were evaluated for Treg reprogramming by in situ hybridization or flow cytometry. Studies in rats and dogs assessed pharmacokinetics and safety. Results MPT-0118 demonstrated dose-dependent in vivo anti-tumor activity. Consistent with the hypothesis that Treg reprogramming supports anti-tumor immunity by initiating IFN-g-driven tumor inflammation, the effect was strongest in combination with anti-PD-1 and in models that are not responsive to ICB alone. MPT-0118-treated tumors showed an increase in IFN-g-secreting Treg, associated with decelerated tumor growth. Ex vivo, MPT-0118 induced Treg reprogramming in tumors resected from patients with colorectal and endometrial cancers. While MPT-0118 caused Treg to produce IFN-g, no changes in the frequencies of Treg circulating in blood were detected in rats. Modeling of the human effective dose and toxicology studies demonstrate a &gt;2x therapeutic window in patients. Conclusions MPT-0118 Treg reprogramming represents a novel strategy with the potential to improve responses to ICB therapy in solid tumors. A Phase 1/1b dose-escalation and cohort-expansion clinical trial evaluating MPT-0018 is underway.
Citation Format: Peter Keller, Irina Mazo, Yun Gao, Vijayapal Reddy, Francisco Caballero, Sam Kazer, Dannah Miller, Roberto Gianani, James E. Marvin, Bret Stephens, Gregory L. Beatty, Ulrich H. von Andrian, Thorsten R. Mempel. Reprogramming regulatory T cells (Treg) using a MALT1 inhibitor for cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P106.
Abstract P110: Neandertal introgressions contribute to upper aero-digestive tract tumor patient survival and identify patients who may benefit from STING agonist treatment
Authors: Gualberto Antonio , Chen Tenghui , Scholz Catherine , Luke Jason 
Published: December 2021

Abstract
Background: Admixture of archaic (Neandertal and Denisova) and ancestral genes enhanced natural immunity during out of Africa migrations and modulates modern susceptibility to autoimmunity and cancer. We investigated a series of functional interactions between archaic and ancestral STING1 and TLR genes to identify vulnerabilities that could be addressed by STING agonist therapy. Methods: Gene variants from 10,389 cancer patients (pts) were obtained from TCGA. Archaic sequences were accessed using UCSD genome browser 410. Linkage disequilibrium was investigated using LDlink v5.0. Patient 1 was treated within NCT04144140. Results: STING1 variants were overrepresented in gastroesophageal cancer pts. V48V (rs7447927-C&gt;G) with GWAS of lower rate of Asian esophageal cancer was in linkage disequilibrium with the reference alleles of the partially active HAQ and REF variants, and with rs13153461, present in Neandertal sequences. STING1 rs7447927-G was also associated with HLA A*24:02 (p&lt;0.001), A*02:06 (p=0.01), and A*31:01 (p=0.02), of Neandertal origin. We then investigated a potential epistasis between STING1 rs7447927-G and TLR variants associated with decreased H. pylori prevalence: Neandertal-like TLR10 I775V (rs4129009) and ancestral TLR6 S249P (rs5743810). No independent prognosis was identified in 32 TCGA legacy studies; however, in upper aerodigestive (oral cavity, oropharynx, esophageal, gastric, biliary tract) tumor pts who carried reference/heterozygous TLR6 S249P and/or reference TLR10 I775, Neandertal-associated STING1 rs7447927-G zygosity was a strong predictor of survival. Hazards ratio for rs7447927-GG vs GC (4.8 vs 2.7 yrs. median survival), and GG vs CC (4.8 vs 1.8 yrs.) were respectively 0.71 and 0.53, N=713, p=0.0003. Patient 1 was a 75 yr.-old male esophageal cancer pt with GERD, Barrett’s esophagus and TLR6 S249/STING1 rs7447927-GC, who was progressing from anti-PD1 and chemotherapy and received 75 microg intra-tumoral injections of the STING agonist E7766. Non treatment-related grade 2 events of anemia and hyponatremia, serum IFNbeta and IP10 levels induction, 20% tumor size reduction including abscopal effects, and 6.3 months PFS benefit were observed. Conclusion: Genotyping of STING1, TLR6-10 variants could contribute to identify pts who may benefit from E7766 treatment.
Citation Format: Antonio Gualberto, Tenghui Chen, Catherine Scholz, Jason Luke. Neandertal introgressions contribute to upper aero-digestive tract tumor patient survival and identify patients who may benefit from STING agonist treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P110.
Abstract P111: Therapeutic KRASG12C inhibition alleviates KRAS-driven immunosuppression
Authors: Mugarza Edurne , Van Maldegem Febe , Boumelha Jesse , Moore Chris , Rana Sareena , Sopena Miriam Llorian , East Phil , Arcas Miriam Molina , Downward Julian 
Published: December 2021

Abstract
Therapeutic KRASG12C inhibitors may substantially improve KRAS-mutant cancer patient care, considering the encouraging clinical data emerging from ongoing clinical trials. Since oncogene-targeting therapies often lead to resistance, the development of combinatorial therapies will be of utmost importance to achieve long-lasting tumour control. Given the known immunosuppressive role of KRAS, clinical trials investigating the combination of KRASG12C inhibitors with immune checkpoint blockade are currently underway for NSCLC patients. Here, we show that KRASG12C inhibition using MRTX1257 alleviates KRAS-driven immune suppression, through a myriad of mechanisms including the augmentation of tumour cell-intrinsic interferon responses. Despite harbouring a large number of somatic mutations, orthotopic 3LL (KRASG12CDNRAS) tumours are able to evade anti-tumour immune responses. Combining multicolour flow cytometry, RNA sequencing and imaging mass cytometry, we observed significantly increased T cell activation and infiltration after MRTX1257 treatment in addition to enhanced antigen presentation cells and gene sets, and reduced myeloid cells, creating an immune permissive microenvironment in these lung tumours. Despite these profound changes, combination of KRASG12C inhibitors and anti-PD-(L)1 antibodies fail to show synergism in our model, in contrast with Amgen’s published data using an immunogenic model of colorectal cancer. This data suggests that a pre-existing anti-tumour immunity may be crucial for clinical responses to KRAS inhibitors and immune checkpoint blockade combinations. Henceforth, ongoing clinical trials investigating this approach will likely only benefit a subset of patients and further research will be needed to examine novel therapeutic approaches and combinations for refractory patients.
Citation Format: Edurne Mugarza, Febe Van Maldegem, Jesse Boumelha, Chris Moore, Sareena Rana, Miriam Llorian Sopena, Phil East, Miriam Molina Arcas, Julian Downward. Therapeutic KRASG12C inhibition alleviates KRAS-driven immunosuppression [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P111.
Abstract P137: SGLT2 inhibition improves BYL719-induced hyperglycemia and hyperinsulinemia in rat pre-clinical models
Authors: Schnell Christian R. , Wyss Daniel , Tinetto Walter , Ferrat Thomas , Gao Jiaping , Darrell Panza , Gold Josh , Beaulieu Valerie , Diener John , Fritsch Christine 
Published: December 2021

Abstract
Background In phase III SOLAR-1 trial (NCT02437318), the PI3K alpha selective inhibitor alpelisib (ALP) + fulvestrant significantly improved progression-free survival vs. fulvestrant alone in patients with HR+/HER2- advanced breast cancer with PIK3CA mutations. Hyperglycemia is an on-target adverse effect of ALP that led to 6% of patient discontinuation in the ALP arm. Recently, Sodium-glucose co-transporter 2 (SGLT2) inhibition was reported to reduce PI3K inhibition-induced glucose and insulin increase. For 6 SOLAR-1 patients, the addition of an SGLT2 inhibitor to metformin (MET) and ALP stabilized blood glucose levels, allowing them to continue ALP treatment. Methods Brown Norway (BN) rat and Rat1-myr-p110α tumor bearing nude rat in vivo models were used to further investigate the degree of glucose and insulin control achievable upon treatment with ALP and a SGLT2 inhibitor dapagliflozin (DAPA) +/- MET and effects on ALP tolerability and efficacy. Results In both rat models tested, the addition of DAPA to ALP nearly suppressed ALP-induced hyperglycemia, was associated with insulin level reduction and insulin sensitivity improvement and no signs for ketoacidosis upon single agent (S.A) nor combination were observed under fed conditions. ALP S.A efficacy in the Rat1-myr-p110α tumor bearing nude rats was maintained when used in combination with DAPA and there was no influence of DAPA on ALP-induced body weight loss (BWL). In BN rats, when combining MET with ALP, a delay in blood glucose reduction was observed vs. DAPA + ALP combination. The triple combination of MET + DAPA + ALP improved further blood glucose levels reduction with the same kinetic as DAPA + ALP. MET + DAPA + ALP triple combination was more effective in reducing plasma insulin levels when compared to MET + ALP or DAPA + ALP double combinations. All combinations tested with MET slightly increased BYL719-induced BWL in BN rats. Conclusions SGLT2 inhibitors such as DAPA significantly reduced hyperglycemia and improved hyperinsulinemia induced by ALP in rat models without further BWL induced by ALP. These results warrant further clinical investigation of adding SGLT2 inhibitors +/- metformin to treat ALP-induced hyperglycemia.
Citation Format: Christian R. Schnell, Daniel Wyss, Walter Tinetto, Thomas Ferrat, Jiaping Gao, Panza Darrell, Josh Gold, Valerie Beaulieu, John Diener, Christine Fritsch. SGLT2 inhibition improves BYL719-induced hyperglycemia and hyperinsulinemia in rat pre-clinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P137.
Abstract P157: Targeting Trop2 for treatment of prostate and breast cancer
Authors: Stoyanova Tanya 
Published: December 2021

Abstract
Background: Prostate cancer and breast cancer are the most commonly diagnosed non-skin cancers and the second leading cause of cancer related mortalities in men and women respectively in the United States. Fifteen percent of breast cancer is TNBC characterized with lack of receptors for estrogen, progesterone, and HER-2/neu making it resistant to hormone therapies and therapies targeting estrogen, progesterone, and HER-2/neu signaling. The first line of treatment for men with advanced prostate cancer is androgen depravation therapy. While initial responses are observed, unfortunately, the disease frequently recurs as a lethal metastatic form referred to as castration-resistant prostate cancer (CRPC). We recently identified that the cell surface receptor, Trop2, is a new regulator of TNBC and CRPC. We demonstrated that Trop2 is highly expressed in CRPC and TNBC. In this study, we set out to test the therapeutic potential of new fully humanized human anti-Trop2 antibody fragments in CRPC and NEPC. Methods: We have generated new human anti-Trop2 antibody fragments. Lentiviral infection was used to generate prostate and breast cancer cell lines with over-expression of Trop2 and knock-down of Trop2. In vivo functional assays were performed including subcutaneous xenograft growth and metastasis. Results: High protein levels of Trop2 are observed in metastatic CRPC and TNBC. Furthermore, loss of Trop2 significantly delays growth, migration and invasion of prostate and breast cancer cells in vitro and delays tumor growth and metastasis of prostate and breast cancer in vivo. Overexpression of Trop2 enhances tumor growth and metastasis of prostate cancer cells and drives CRPC. We generated new fully humanized human anti-Trop2 antibody fragments that have therapeutic efficacy in preclinical models of prostate and breast cancers. Conclusions: In a previous study, we identified cell surface receptor, Trop2, as a novel driver of metastatic CRPC. Herein, our new findings reveal that Trop2 represents a promising therapeutic target for prostate, breast, and potentially other epithelial cancers. We identified lead antibody candidates that bind to human Trop2 protein with high affinity and stability. Furthermore, our lead anti-Trop2 Abs significantly delay the tumors growth in CRPC and TNBC without measurable toxicity and provide new therapeutic strategy for metastatic CRPC and TNBC.
Citation Format: Tanya Stoyanova. Targeting Trop2 for treatment of prostate and breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P157.