bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1079: Combination of tipifarnib with KRAS G12C inhibitors to prevent adaptive resistance
Authors: Patel Hetika Vora , Smith Alison , Chan Stacia , Kessler Linda , Burrows Francis , Malik Shivani 
Published: April 2023

Abstract
Selective KRAS G12C inhibitors, including AMG510 (sotorasib) and MRTX849 (adagrasib), have exhibited clinical activity in patients with non-small cell lung cancer (NSCLC); however, drug resistance and relapse inevitably occur through various mechanisms, which limits the ability of these therapeutic agents to achieve durable responses. Resistance mechanisms include feedback reactivation of compensatory, oncogenic signaling pathways and the attainment of a drug-tolerant state, each of which allows cancer cells to survive the anti-tumor effects of these highly active drugs. Compensatory mechanisms ameliorating KRAS blockade include HRAS/NRAS and the PI3K-AKT-mTOR pathway. Tipifarnib is a clinical stage farnesyltransferase inhibitor known to inhibit multiple farnesylation-dependent proteins in tumor cells. We have recently shown that tipifarnib can prevent feedback-mediated adaptive resistance to the PI3Kα inhibitor, alpelisib, through inhibition of both HRAS and RHEB, allowing simultaneous blockade of two key nodes of the oncogenic MAPK- and PI3K-signaling pathways. In another example, tipifarnib has been demonstrated by others to inhibit the ability of tumor cells to enter a drug-tolerant state induced by the EGFR inhibitor, osimertinib, in EGFR-mutant NSCLC models. In these models, inhibition of farnesylation of certain RHO proteins appear to contribute to the death of drug-tolerant cells prior to the emergence of acquired resistance mutations. Building on these two mechanisms of how tipifarnib may prevent adaptive resistance, we propose that tipifarnib can be used as an effective partner drug to delay or prevent the onset of adaptive resistance to KRAS G12C inhibitors. We have conducted in vitro 2D and 3D viability and regrowth experiments using combinations of tipifarnib with KRAS G12C inhibitors and have observed synergistic, anti-proliferative effects in KRAS G12C NSCLC cell lines as well as enhanced activity of combination in a KRAS G12C NSCLC PDX model. We are currently expanding the scope of in vitro and in vivo combination studies to further evaluate the molecular mechanism(s) of resistance that tipifarnib targets when combined with KRAS G12C inhibitors.
Citation Format: Hetika Vora Patel, Alison Smith, Stacia Chan, Linda Kessler, Francis Burrows, Shivani Malik. Combination of tipifarnib with KRAS G12C inhibitors to prevent adaptive resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1079.
Abstract 2191: Detection of actionable lung cancer fusion genes with known and novel partners from highly degraded FFPE material
Authors: Lee Bongyong , Babu Alisha , Zhang Aiguo , Sha Michael Y. 
Published: April 2023

Abstract
Chromosomal rearrangements resulting in expression of oncogenic chimeric proteins drive tumor progression. Gene fusions are promising targets for cancer therapy in various types of cancers. Therefore, faithful detection of gene fusions is essential in precision medicine. Previously, fusions have been detected using FISH, RT-PCR and RNA-seq. Targeted sequencing provides better sensitivity as only the regions associated with the driver genes are sequenced, increasing possible coverage depth, and reducing cost. We developed a targeted RNA-based lung cancer fusion panel utilizing 5’ RACE technology to construct a NGS library for detection of fusion transcripts present in total RNA from highly degraded samples, such as blood or FFPE samples. The panel is deliberately designed to cover 64 known actionable fusion genes as well as novel gene fusions. Using an in-house fusion RNA mix comprising of 52 fusion transcripts, the panel was optimized and balanced. A total of 40 lung cancer patient FFPE samples, one 6-fusion FFPE reference sample and three fusion positive cell line samples were used for validating the panel. Limit of detection (LoD) was determined using the in-house RNA mix and normal lung tissue RNA. The minimum RNA input to detect all 52 fusion transcripts was 10-4 ng (0.1 pg) of mixture of RNAs in background of 10 ng of normal lung tissue RNA. The panel successfully detected all six fusion transcripts with 10 ng of RNA from a 6-fusion reference FFPE sample. With this confirmation, we tested clinically relevant sample types which are damaged RNAs from FFPE material. This study demonstrates the performance of our newly developed NGS fusion gene panel with clinical samples. It accommodates highly degraded RNA samples with low amounts of input. The next step would be to expand the testing to include more samples and cell-free RNAs.
Citation Format: Bongyong Lee, Alisha Babu, Aiguo Zhang, Michael Y. Sha. Detection of actionable lung cancer fusion genes with known and novel partners from highly degraded FFPE material [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2191.
Abstract 2771: KSQ-4279 mediated USP1 inhibition induces replication associated DNA gaps that contribute to cell death
Authors: Nayak Sumeet , Sullivan Pamela , Mishina Yuji , Dodson Anne , Kao Pei-Lun , Gannon Hugh , Middleton Chris , Shenker Sol , Murray Morgan , Schlabach Michael , Stegmeier Frank , Tobin Erica , Cadzow Louise , Wylie Andrew 
Published: April 2023

Abstract
Tumors with defects in DNA double strand break (DSB) repair pathways, including those with mutations in BRCA1/2, are often treated with either poly (ADP-ribose) polymerase-1 (PARP1) inhibitors or platinum-based chemotherapy. Despite their clinical benefits, many patients develop resistance leading to the need for novel therapeutic approaches. To address this unmet clinical need, we applied our CRISPRomics® platform to identify novel therapeutic targets for DNA damage and repair deficient cancers. One of the top ranked targets was the deubiquitinating enzyme, USP1, with known functions in DNA damage repair pathways of translesion synthesis (TLS) and fanconi anemia (FA). We developed a novel small molecule inhibitor, KSQ-4279, that selectively inhibits USP1 and leads to accumulation of mono-ubiquitinated USP1 substrates such as proliferating nuclear antigen (PCNA). In addition to KSQ-4279’s activity in BRCA mutant tumors with known homologous recombination deficiencies (HRD), KSQ-4279 also exhibits synergistic activity in combination with PARP inhibitors and re-sensitizes PARP refractory tumors. Mechanistically, we show that in sensitive cell lines, treatment with KSQ-4279 alters the replication fork dynamics resulting in replication stress via induction of replication associated single stranded DNA gaps and subsequent fork degradation. Additionally, KSQ-4279 leads to loss of the essential DNA replication and repair protein, PCNA, which can be rescued by blocking PCNA ubiquitination either through Rad18 knockout or by ectopic expression of a PCNA K164R mutant. This loss of PCNA and sensitizing ssDNA lesions eventually lead to DNA double strand breaks (DSBs) and wide-spread DNA damage accumulation that contributes to cell death. This mechanistic insight supports the ongoing clinical trial of KSQ-4279 in patients with tumors harboring BRCA1/2 or other HRD mutations, both as a single agent and in combination with PARP inhibitors.
Citation Format: Sumeet Nayak, Pamela Sullivan, Yuji Mishina, Anne Dodson, Pei-Lun Kao, Hugh Gannon, Chris Middleton, Sol Shenker, Morgan Murray, Michael Schlabach, Frank Stegmeier, Erica Tobin, Louise Cadzow, Andrew Wylie. KSQ-4279 mediated USP1 inhibition induces replication associated DNA gaps that contribute to cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2771.
Abstract 3035: Phase I trial of alpha-lactalbumin vaccine in high-risk operable triple-negative breast cancer
Authors: Budd George Thomas , Johnson Justin M. , Rhoades Emily , Moore Halle , Levengood Holly , Kruse Megan , Roesch Erin , Abraham Jame , Elliott Brenna , Haury Elena , Swartz Rachel , Pederson Holly , Hilli Zahraa Al , Tuohy Vincent 
Published: April 2023

Abstract
Background: Triple-negative breast cancer (TNBC) has a poor prognosis and may be associated with germline mutations. α-lactalbumin (aLA) is expressed in lactating breasts but not at other times or in other tissues. Expression of aLA is found in 70% of TNBC (PMID: 27322324) so could be an immunologic target for TNBC based on the “retired protein hypothesis” (PMID: 31926646). In pre-clinical studies vaccination with aLA inhibited growth of established breast tumors and provided protection from development of autochthonous tumors in transgenic murine models of breast cancer and against 4T1 transplantable breast cancer in BALB/c mice (PMID: 20512124).
Methods: To determine the safety and immunogenicity of aLA, patients with early stage TNBC are being entered in a Phase I trial of aLA with GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Subjects receive 3 vaccinations given once every 2 weeks. Events of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2 are considered dose-limiting toxicities (DLTs).
Results: CTCAE toxicity by dose level is summarized below. All DLTs were injection site reactions, with ulceration and need for incisional drainage representing the grade 3 events. ELISpot assays to determine frequencies of T-cells producing IFN-γ and IL-17 in response to recombinant aLA and ELISA assays of antibody response to aLA will be available in December 2022.
Conclusion: Dose level 2 appears to be the maximum tolerated dose. Accrual to dose levels 1 and 2 will be expanded to further define toxicity and immunologic effects. Accrual of patients with BRCA1 or PALB2 mutations planning to undergo prophylactic mastectomy is beginning in order to define the toxicity and immunologic effects in this group and to determine whether inflammatory changes from occult lactational foci will be produced.
Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593)
Worst Toxicity by Dose Level Dose Level aLAC (mcg) dose Zymosan (mcg) dose n Patients n Grade 0 n Grade 1 n Grade 2 n Grade 3 1 10 10 3 3 2 100 10 3 3 3 500 10 3 2 1 Original 2 100 100 1 1
Citation Format: George Thomas Budd, Justin M. Johnson, Emily Rhoades, Halle Moore, Holly Levengood, Megan Kruse, Erin Roesch, Jame Abraham, Brenna Elliott, Elena Haury, Rachel Swartz, Holly Pederson, Zahraa Al Hilli, Vincent Tuohy. Phase I trial of alpha-lactalbumin vaccine in high-risk operable triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3035.
Abstract 4195: Spatially resolved single cell transcriptomic profiling in formalin-fixed paraffin-embedded (FFPE) tissues
Authors: He Jiang , He Justin , Wiggin Timothy , Foreman Rob , Chen Renchao , Fernandez Nicolas , Emanuel George 
Published: April 2023

Abstract
Formalin-fixed paraffin-embedded (FFPE) tissues are the most widely used clinical sample types in histology and molecular diagnosis, but these samples are often challenging for single-cell transcriptomic analysis due to RNA degradation and protein crosslinking. A spatial transcriptomics technique with high detection efficiency and single molecule resolution is required in order to accurately profile the gene expression in FFPE samples in situ. Vizgen’s MERSCOPE platform, built on multiplexed error robust in situ hybridization MERFISH technology, directly profiles intact tissue’s transcriptome with subcellular spatial resolution. Here, we demonstrate the FFPE MERSCOPE workflow in tissues from 10 mouse and human samples, including archival clinical samples. In each sample, hundreds of thousands of cells were captured with &gt;100 million transcript counts, generating detailed spatial transcriptomic data for the profiled genes in each sample. A comparison of FFPE and matched fresh frozen samples indicated that the FFPE workflow performs similarly in detection efficiency as compared to the fresh frozen protocol. We further demonstrated the MERSCOPE FFPE workflow is compatible with protein imaging by performing simultaneous protein-based cell boundary staining with MERFISH to accurately profile gene expression and map cell types in archival clinical human samples. Finally, we constructed a spatially resolved single cell atlas across eight major tumor types, mapped and cataloged different cell types within the tumor microenvironment and systematically characterized the gene expression among cells. This study demonstrates the potential for spatially resolved transcriptomic profiling of FFPE samples at single cell level to contribute to a wide range of biomedical research areas, including many applications to study human diseases.
Citation Format: Jiang He, Justin He, Timothy Wiggin, Rob Foreman, Renchao Chen, Nicolas Fernandez, George Emanuel. Spatially resolved single cell transcriptomic profiling in formalin-fixed paraffin-embedded (FFPE) tissues. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4195.
Abstract 4482: Discovery of GH2616, a potent and selective KIF18A inhibitor with robust in vivo efficacy in p53 mutant cancer
Authors: Li Jie Jack , Zhang Guiping , Li Jiapeng 
Published: April 2023

Abstract
Chromosomal instability (CIN) is one of the hallmarks of cancer. Cancer cells often undergo whole-genome doubling (WGD) and P53 represents a major barrier to the proliferation of WGD+ cells. Therefore, cancer cells with either CIN or WGD often harbor the p53 mutation. Recently, KIF18A has emerged as a potential therapeutic target in CIN or WGD cancer cells. We have identified a potent and selective KIF18A inhibitor, GH2616. In vitro, GH2616 inhibited the kinesin motor activity with an IC50 less than 50 nM, and with an EC50 less than 50 nM in the mitotic index assay using HT29 cells (WGD). In vivo, GH2616 inhibited the growth of WGD CDX models with a dose dependent manner. GH2616 has good oral bioavailability in different species and metabolic stability for QD dosing. This compound also showed low potential of DDI thus suitable for drug combinations. In a cell panel with more than 200 cell lines, GH2616 selectively inhibit the growth of cells with p53 mutant and some other specific biomarkers in multiple tumor types. In conclusion, we discovered GH2616 as a novel KIF18A inhibitor with potent in vivo efficacy. It is currently under evaluation in IND-enabling studies and IND filing is expected in Q4, 2023.
Citation Format: Jie Jack Li, Guiping Zhang, Jiapeng Li. Discovery of GH2616, a potent and selective KIF18A inhibitor with robust in vivo efficacy in p53 mutant cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4482.
Abstract 4989: Discovery and evaluation of ISM6466A, a novel covalent CDK12 inhibitor for the treatment of cancer
Authors: Min Lihua , Lu Hongfu , Zhang Yihong , Wu Jianping , Cai Xin , Zheng Min , Cui Hui , Qiao Junwen , Ding Xiao , Rao Sujata , Ren Feng , Zhavoronkov Alex 
Published: April 2023

Abstract
Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases. The CDK12/cyclin K complex regulates the elongation step of RNA transcription by phosphorylating Ser2 on the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II, and selectively affects the expression of genes, such as BRCA1 and BRCA2, involved in DNA Damage Response (DDR). CDK12 mutations as well as overexpression have been reported in different types of malignancies, making it an attractive cancer target. In this study, a series of covalent CDK12 inhibitors were designed and profiled in biochemical and cellular assays. ISM6466A was identified as a lead compound, demonstrating good in vitro efficacy, ADME properties, safety pharmacology profile (e.g., CYP, hERG), and a reasonable in vivo PK profile. Biochemically, ISM6466A exhibited reasonable selectivity over other CDKs, and inhibited cell proliferation in a panel of tumor cell lines with IC50 values in the nanomolar range (e.g., IC50 of ~100nM in the TNBC and AML cell lines, SUM149PT and MV4-11, respectively). Cell-based assays showed that ISM6466A has a selective inhibitory action for the phosphorylation of Ser2 on the CTD, but not for that of Ser5 or Ser7. Notably, ISM6466A demonstrated excellent in vivo anti-tumor efficacy in the SUM149PT breast cancer CDX model (Tumor Growth Inhibition, TGI, of 114% at 60 mg/kg QD) and in the MV4-11 AML CDX model (TGI of 95% at 30 mg/kg QD), without body weight loss. Data from an endpoint PKPD study in the MV4-11 CDX model revealed that ISM6466A inhibited phosphorylation of Ser2 on the CTD, and also inhibited DDR genes such as BRCA1 and ATR. Results from a 28-day rat DRF study revealed that the compound did not show evident signs of toxicity at the tested doses, suggesting a reasonable safety window for ISM6466A.In summary, the novel, covalent, small-molecule CDK12 inhibitor, ISM6466A, demonstrated excellent preclinical efficacy along with favorable drug-like properties. Our results underscore the therapeutic potential of ISM6466A for the treatment of cancer.
Citation Format: Lihua Min, Hongfu Lu, Yihong Zhang, Jianping Wu, Xin Cai, Min Zheng, Hui Cui, Junwen Qiao, Xiao Ding, Sujata Rao, Feng Ren, Alex Zhavoronkov. Discovery and evaluation of ISM6466A, a novel covalent CDK12 inhibitor for the treatment of cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4989.
Abstract 5009: Inhibition of TGFBR2 signaling re-sensitizes TMZ-resistant glioblastoma cells to therapy
Authors: Johnson Maya K. , Korleski Jack , Johnson Amanda , Sall Sophie , Laterra John , Lopez-Bertoni Hernando 
Published: April 2023

Abstract
Glioblastoma (GBM), the most aggressive and lethal form of brain tumors, recurs in 90% of cases and the standard protocol of care—temozolomide (TMZ)—is an ineffective method to combat chemo-resistant GBM. It is therefore imperative that we identify, develop, and design novel therapeutics to effectively combat recurrent GBM (rGBM). Multi-potent stem-like cell subpopulations within GBM (also referred to as glioma stem cells or GSCs) play important roles in tumor propagation, therapeutic resistance, and recurrence following treatment. Understanding the molecular mechanisms that drive resistance in GSCs can lead to novel therapeutic approaches for rGBM. Bioinformatics analyses of transcriptome data sets from rGBM clinical specimens identified transforming growth factor-beta receptor type 2 (TGFBR2) as a putative driver of resistance and recurrence in GBM. We show that TMZ-resistant cells become more stem-like concurrent with higher expression of TGFBR2 protein and mRNA. Importantly, shRNA-mediated inhibition of TGFBR2 decreases proliferation of TMZ-resistant cells and enhances the effects of TMZ. We hypothesize that by developing targeted therapeutics to reduce TGFBR2 expression we will inhibit the growth capacity and/or re-sensitize rGBM cells to ionizing radiation (IR) or TMZ treatment by simultaneously targeting multiple putative oncogenes implicated in the induction of stem-like resistant GBM cell subsets. Future directions include inhibiting TGFBR2 signaling in clinical specimens derived from rGBM patients using two translatable approaches: (1) ITD1, a small molecule TGFBR2 inhibitor predicted to cross the blood-brain-barrier and (2) microRNAs to target multiple TGFBR2 target genes up-regulated in rGBM.
Citation Format: Maya K. Johnson, Jack Korleski, Amanda Johnson, Sophie Sall, John Laterra, Hernando Lopez-Bertoni. Inhibition of TGFBR2 signaling re-sensitizes TMZ-resistant glioblastoma cells to therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5009.
Abstract 822: Target-specific nanoparticle-based strategy for improved therapeutic efficacy to treat pancreatic cancer
Authors: Vivero-Escoto Juan Luis , Tarannum Mubin , Mukherjee Pinku 
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of the pancreatic cancer cases and is the fourth-leading cause of cancer-related mortality. Unfortunately, despite the tremendous scientific efforts, it is shocking to note that PDAC has the worst prognosis with 5-year survival rate of 10% which has not significantly improved from the past 40 years. The high mortality and awful prognosis of PDAC can be attributed to multifactorial reasons like its intrinsic and acquired resistant behavior, early micrometastatic dissemination, desmoplastic effect and heterogeneities in tumors, rendering the current treatments rather ineffective. Developing reliable methods for the effective treatment of PDAC will have a major impact on the clinical outcome for this deadly disease. Nanoparticle-based drug delivery using mesoporous silica nanoparticles (MSNs) can be a potential alternative for the treatment of PDAC owing to their outstanding properties such as high surface area, tunable pore diameters, external and internal surface, which make this platform suitable for high drug loading and functionalization. We have designed, synthesized and characterized a target-specific, stimuli-responsive MSN platform for the controlled delivery of cisplatin (cisPt) and gemcitabine (Gem) (TAB004-Gem-cisPt-MSNs) with an optimal drug ratio. Our results demonstrate that this delivery system effectively targets tumor associated MUC1 (tMUC1), increases therapeutic efficiency with reduced toxicity in both a syngeneic and a spontaneous mouse model that overexpressed tMUC1. Moreover, the same MSN platform has been used in a sequential treatment where MSNs containing a Sonic Hedgehog (SHh) inhibitor, cyclopamine (CyP), and the Gem-cisPt-MSNs as the main delivery system led to reduction in the tumor stroma along with an improvement in the treatment of PDAC. Taken together, our findings support the potential of drug delivery using MSN nanoparticles for stroma modulation and to prevent pancreatic cancer progression.
Citation Format: Juan Luis Vivero-Escoto, Mubin Tarannum, Pinku Mukherjee. Target-specific nanoparticle-based strategy for improved therapeutic efficacy to treat pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 822.