bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 7145: Identification of Debio 0432 as a potent and selective USP1 inhibitor for cancer therapy
Authors: Luong Noemie , Kunze Annett , Quesnot Nicolas , Aho Erin R. , Berry Loren , Boiko Scott , Buckmelter Alex J. , Lofek Sebastien , Vigano Selena , Chardonnens Christophe
Published: March 2024

Introduction: Debio 0432 is a Ubiquitin Specific Protease 1 (USP1) inhibitor at preclinical stage. This study presents the first data on this small molecule and its activity as an anti-cancer therapy in multiple preclinical models. USP1 is a deubiquitinase, member of the deubiquitinating enzyme (DUB) family that plays an important role at the replication fork during DNA replication. Its prominent role in DNA repair, targeting Proliferating Cell Nuclear Antigen (PCNA) that regulates polymerase recruitment in the translesion synthesis (TLS), makes it an emergent target in the DNA damage repair (DDR) field.

Methods: In silico docking has been used to identify a likely binding site of Debio 0432. Biochemical and cellular assays have been performed to show its activity on the target and in cell lines of different cancer types. In vivo models in cell line derived xenograft (CDX) and patient derived xenograft (PDX) were then used to confirm the activity of the compound and to study PK/PD relationship.

Results: Debio 0432 likely binds USP1 in an allosteric pocket and is very selective across the 58 members of the USP family. Furthermore, it does not affect any kinase. Its biochemical activity on USP1 is in the low nanomolar range and cellular activity ranges between from single digit nM to above 1uM. In vivo, Debio 0432 shows antitumor activity in the BRCA mutant breast cancer model MDA-MB-436. The downstream target Ub-PCNA, selected as pharmacodynamic marker, is modulated in a dose and plasma exposure-dependent manner. Further in vivo experiments in PDX models showed dose-dependent activity in different cancer types, in both BRCA wild type and mutant models. Treatments in all in vivo studies were well tolerated.

Conclusion: Overall, we show that Debio 0432 is a selective and potent small molecule targeting USP1, an emerging target in the DDR field. It shows good activity in different preclinical models and is well tolerated at active doses. Debio 0432 is currently undergoing IND-enabling studies and in preparation for entry into clinical development.

Citation Format: Noemie Luong, Annett Kunze, Nicolas Quesnot, Erin R. Aho, Loren Berry, Scott Boiko, Alex J. Buckmelter, Sebastien Lofek, Selena Vigano, Christophe Chardonnens. Identification of Debio 0432 as a potent and selective USP1 inhibitor for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7145.
Abstract 7146: HSK39775: A USP1 inhibitor for the treatment of cancers with homologous recombination deficiencies
Authors: Xu Jun , Li Yangguang , Wang Ju , Tang Pingming , Wang Jianmin , Zhang Chen , Yan Pangke
Published: March 2024

Tumors with BRCA1/2 mutations or homologous repair deficiency (HRD) are vulnerable to agents that target DNA repair pathways, including platinum-containing chemotherapeutics and poly (ADP-ribose) polymerase-1 (PARP1) inhibitors. Despite the significant therapeutic benefits in patients with BRCAm or HRD, innate and acquired resistance to PARPi is still a challenge in the clinic. To address this clinical challenge, we developed HSK39775, a potent, highly selective inhibitor of ubiquitin carboxyl-terminal hydrolase 1 (USP1), which acts as an oncogenic and PARP inhibitor resistance driver involved in DNA damage repair pathway through the deubiquitylation of proteins in Translesion Synthesis pathway and Fanconi Anemia pathway, paired with BRCA as a synthetic lethality target. HSK39775 was active in enzymatic level to inhibit USP1/UAF1 complex. Enzymatic panel screening containing 50 deubiquitinase demonstrated high selectivity of HSK39775. Ubiquitinated PCNA was accumulated treated by HSK39775, indicating target engagement. HSK39775 also demonstrated potent anti-proliferation activity against cancer cell lines with BRCA mutation and excellent selectivity between BRCA WT vs. BRCAm. Combining HSK39775 with PARP inhibitors indicated synergy in cell lines with partial or insensitivity to each agent alone. Triple-negative BRCA mutant breast cancer xenograft model demonstrated strong dose-dependent tumor growth inhibition of HSK39775 as a single agent with Tumor Growth Inhibition (TGI) of 63.2% at 30 mg/kg QD, and ubiquitinated PCNA was also accumulated in HSK39775 treated tumor tissue. Meanwhile, combination with PARP inhibitors significantly enhanced the therapeutic efficacy of HSK39775 in xenograft model and led to tumor regressions and durable tumor control even at low dose (TGI:89% (HSK39775, 5 mg/kg + Olaparib, 50 mg/kg)). Interestingly, HSK39775 inhibited the tumor growth of a HRP and BRCA wild-type lung cancer xenograft as a single agent with TGI of 94% at 30 mg/kg QD, suggesting the therapeutic effect of USP1 inhibitors beyond canonical BRCA mutant or HRD tumors. In summary, these results indicate HSK39775 as a potent and selective USP1 inhibitor and support further development.

Citation Format: Jun Xu, Yangguang Li, Ju Wang, Pingming Tang, Jianmin Wang, Chen Zhang, Pangke Yan. HSK39775: A USP1 inhibitor for the treatment of cancers with homologous recombination deficiencies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7146.
Abstract 7170: Pharmacokinetic profiling of Re-Phenformin in vivo: A novel approach in pancreatic cancer therapy
Authors: Gholizadeh Amir Mohammad , Dai Lu , Dagher Fatima , Xiong Chiyi , Li Chun , Chow Diana S-L
Published: March 2024

Phenformin, a biguanide medication, has long been utilized in the treatment of diabetes. Recent research indicates that phenformin may also serve as an effective anticancer agent. This study introduces the synthesis and evaluation of Re tricarbonyl phenformin complex (Re-(CO)3-Phenformin, Re-Phen), as a derivative of Phenformin and novel anticancer agent for pancreatic cancer treatment. Re-Phen was synthesized, purified, and characterized through preparative HPLC, NMR, mass spectrometry, and FT-IR. Subsequent in vitro studies, utilizing the MTS assay, assessed its cytotoxicity against pancreatic cancer cell lines, including Kras* murine PDAC and MiaPaca-2 human PDAC. Notably, Re-Phen exhibited significantly higher cytotoxic effects in MiaPaca-2 cells (IC50= 0.755 mM) and Kras* cells (IC50= 0.410 mM) compared to Phenformin treatment (IC50= 4.02 mM and 2.36 mM, respectively). These results highlight Re-Phen's enhanced anticancer activity, outperforming Phenformin in potency. Further investigation into the pharmacokinetics of Re-Phen involved an in vivo study with rats intravenously administered 2 mg/kg of Re-Phenformin. Blood samples were collected at intervals (10 min to 24 h post-dose) and were analyzed by validated LC-MS/MS. The pharmacokinetic profile of Re-Phen was best described by a 2-compartment model, using Phoenix® WinNonlin (version 8.0), with a particular focus on comparing the profiles of Phenformin and Re-Phen. The study revealed that Re-Phen has a significantly extended half-life compared to Phenformin (9.13 hr vs 2.11 hr), indicating prolonged systemic retention. Additionally, Re-Phen demonstrated an increased area under the curve (AUC), suggesting greater systemic exposure at equivalent dosing (90.55 hr*ng/ml vs 7.13 hr*ng/ml). This could imply enhanced bioavailability or altered metabolic clearance of Re-Phen compared to its parent compound. The two-Compartment of Re-Phe, provide a deeper understanding of its pharmacokinetic characteristics. In conclusion, Re-Phen not only demonstrates superior anticancer efficacy in vitro but also exhibits a more favorable pharmacokinetic profile in vivo. The extended half-life and increased AUC of Re-Phen suggest the potential of offering improved therapeutic efficacy in pancreatic cancer treatment. These promising findings warrant further investigation and could position Re-Phen as a promising therapeutic agent for the pharmacological management of pancreatic cancer.

Citation Format: Amir Mohammad Gholizadeh, Lu Dai, Fatima Dagher, Chiyi Xiong, Chun Li, Diana S-L Chow. Pharmacokinetic profiling of Re-Phenformin in vivo: A novel approach in pancreatic cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7170.
Abstract 7222: Antiandrogen equipped with HDAC inhibitors activates autophagy-mediated growth inhibition in castrate-resistant prostate cancer
Authors: Chandrasekaran Balaji , Yalla Kiran Kumar , Tyagi Ashish , Shukla Vaibhav , Tyagi Neha , Tyagi Bhawna , Vashishta Mohit , Oyelere Adegboyega K , Damodaran Chendil
Published: March 2024

Targeting androgen receptor (AR) by pharmacologic intervention is one of the practical approaches for the treatment of castration-resistant prostate cancer (CRPC). Hence, this study aimed to develop novel molecules that employ multiple mechanisms to inhibit AR expression and curtail the growth of CRPC. The target antiandrogen-equipped histone deacetylase inhibitors were synthesized, adapting the convergent chemistry we used to synthesize the first-generation compounds. The final compounds were characterized using 1H-NMR, 13C-NMR, and high-resolution mass spectrometry. We synthesized and analyzed several compounds, in which KK62 emerged as the lead compound. KK62 significantly inhibits a panel of CRPC cell lines in nanomolar concentrations without causing toxicity to healthy prostate epithelial cells. The molecular analysis suggested that inhibition of AR and AR-splice variants was evident, followed by downregulation of PSA expression in AR-positive CRPC cell lines. Further analysis confirmed that KK62 overcomes dihydrotestosterone (DHT) induced AR signaling and enzalutamide-resistant CRPC cells by downregulating AR and AR-splice variants in CRPC cells. Subsequent analysis confirmed that KK62 induces autophagy signaling by upregulating autophagosome (LC3B) and lysosome (LAMP1) markers expression and facilitating the autophagosome and lysosome fusion, which resulted in the induction of apoptosis in all AR-positive CRPC cell lines. The pro-apoptotic markers, such as BAX and cleaved caspase, were upregulated, whereas the downregulation of pro-survival markers was evident in KK62-treated CRPC cells. Our ongoing castrated and non-castrated xenotransplanted CRPC tumors and Patient-derived xenograft in vivo studies would validate our in vitro findings and confirm that KK62 is a potent compound that may improve therapeutic advances in treating CRPC.

Citation Format: Balaji Chandrasekaran, Kiran Kumar Yalla, Ashish Tyagi, Vaibhav Shukla, Neha Tyagi, Bhawna Tyagi, Mohit Vashishta, Adegboyega K Oyelere, Chendil Damodaran. Antiandrogen equipped with HDAC inhibitors activates autophagy-mediated growth inhibition in castrate-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7222.
Abstract 7257: Examining the promise of precision medicine in immuno-oncology: Vectors for targeted therapeutic delivery
Authors: Richardson Crystal , Rao Prassanna , Koole Cassandra , Karney Michael J. , Kumar Sumit
Published: March 2024

At the forefront of therapeutic delivery is an array of vectors and targeting methods that hold immense promise for precision medicine. Vehicles such as viral vectors (AAV and lentivirus), lipid nanoparticles (LNPs) or liposomes, and peptide micelles each possess distinct and inherent properties, empowering researchers with tools to navigate the intricate challenges of specificity and efficiency in drug transport. Herein, we discuss and demonstrate design principles underpinning these vectors, elucidating their unique mechanisms for targeted delivery including:- A high-throughput viral packaging process to enable rapid downstream CRISPR or shRNA screening- Proprietary AAV plasmid synthesis and preparation techniques to maintain ITR integrity and improve gene delivery- Rapid synthesis, in vitro transcription, and novel sequencing of mRNA constructs for complete characterization of critical components such as the polyA tailBy synthesizing advancements in vector technologies, this poster serves as a roadmap for researchers and practitioners navigating the evolving landscape of targeted drug delivery in immuno-oncology.

Citation Format: Crystal Richardson, Prassanna Rao, Cassandra Koole, Michael J. Karney, Sumit Kumar. Examining the promise of precision medicine in immuno-oncology: Vectors for targeted therapeutic delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7257.
Abstract 7268: The SOS1 inhibitor MRTX0902 demonstrates activity across cancer models with mutations in proximal components of the RAS-MAPK pathway
Authors: Sudhakar Niranjan , Yan Larry , Qiryaqos Fadia , Laguer Jade , Briere David , Hebbert Allan , Calinisan Andrew , Coma Silvia , Pachter Jonathan , Christensen James G. , Olson Peter , Khare Shilpi
Published: March 2024

Genetic alterations in the RAS-MAPK pathway are one of the most frequent causes of human cancers. While targeted therapies are approved for patients harboring mutations in KRAS G12C in advanced or metastatic non-small cell lung cancer, there remains a need for an effective therapy for cancers characterized by additional RAS-MAPK pathway mutations across cancer types. Previous studies have shown that genetic or pharmacological inhibition of Son of Sevenless homolog 1 (SOS1) demonstrates antiproliferative activity in cancer cells addicted to KRAS signaling, including cell lines with oncogenic mutations in KRAS, SOS1, PTPN11, or EGFR or a loss-of-function mutation in NF1. These genetic alterations each function to increase SOS1-mediated GTP-loading of KRAS and increase signaling flux through the MAPK pathway. Inhibition of SOS1 by MRTX0902 is anticipated to shift the tumor cell equilibrium of KRAS towards the inactive GDP-bound KRAS, leading to MAPK pathway inhibition. MRTX0902 is a selective inhibitor of SOS1 under evaluation in clinical trials for the treatment of advanced, unresectable, or metastatic cancers with mutations in the KRAS-MAPK pathway. In the present studies, we have shown that MRTX0902 demonstrates single-agent anti-proliferative activity and modulates ERK1/2 phosphorylation (pERK) across a panel of human tumor cell lines harboring oncogenic mutations in SOS1, PTPN11, BRAF (class III) and NF1. Furthermore, oral administration of MRTX0902 as a monotherapy in preclinical human tumor cell-derived xenograft models harboring these oncogenic mutations results in significant tumor growth inhibition. Additionally, combination with the RAF/MEK clamp avutometinib demonstrated greater antitumor activity versus either monotherapy treatment. These data support the clinical utility of MRTX0902 as a single agent or combination partner of avutometinib for the treatment of human cancers harboring oncogenic mutations implicated in dysregulation of RAS-dependent signaling including SOS1, PTPN11, NF1, and BRAF (class III).

Citation Format: Niranjan Sudhakar, Larry Yan, Fadia Qiryaqos, Jade Laguer, David Briere, Allan Hebbert, Andrew Calinisan, Silvia Coma, Jonathan Pachter, James G. Christensen, Peter Olson, Shilpi Khare. The SOS1 inhibitor MRTX0902 demonstrates activity across cancer models with mutations in proximal components of the RAS-MAPK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7268.
Abstract 7295: A novel XNA technology-based assay to detect JAK2 V617F mutation by real-time PCR
Authors: Shen Shuo , Brown Robert , Kim Daniel , Pastor Larry , Fu Andrew Y. , Kaur Pushpinder , Babu Alisha , Liu Wei , Zhang Aiguo , Tanaka Hiromi , Sha Michael Y.
Published: March 2024

The Janus kinase 2 (JAK2) gene is located on chromosome 9p24.1 and encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signaling. The JAK2 protein is especially important for controlling the production of blood cells from hematopoietic stem cells. In fact, the JAK2 mutation at amino acid 617 (Valine 617 to Phenylalanine, V617F) is the most frequently detected mutation in myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). This dominant gain-of-function V617F mutation results in constitutive tyrosine phosphorylation activity, leading to uncontrolled blood cell production, including increased numbers of erythrocytes, neutrophils, and platelets. To detect the JAK2 V617F mutation in DNA from patient blood samples, we developed a unique real-time PCR assay using our proprietary XNA technology that enables the assay to selectively amplify the mutant sequence by using a synthetic DNA analog XNA (Xenonucleic Acid). The JAK2 V617F mutation detection assay is designed to detect a valine-to-phenylalanine mutation at amino acid 617 (V617F). PCR primers, TaqMan probes, and XNA were designed for the JAK2 V617F mutation, along with primers and probes for an internal control gene in the duplex setting. The analytical performance of the assay was verified and validated using a variety of control samples. The results revealed that the XNA completely suppressed the amplification of wildtype sequence while only the V617F mutant sequence was amplified. The JAK2 V617F mutation detection assay is highly reproducible with intra- and inter-assay coefficients of variation of less than 10%. Results for the assay’s analytical sensitivity indicated that V617F could be detected with about 0.25% mutant allele frequency in 10 ng DNA input. In addition, no significant cross-amplification between V617F and V617I was observed. Thus, the JAK2 V617F mutation detection assay is specific for the V617F mutation. The JAK2 V617F mutation detection assay, using XNA-based technology, provides high sensitivity and specificity to detect the JAK2 V617F mutation. Thus, this assay would be a useful tool for clinical decision-making in determining the presence of the JAK2 V617F mutation in DNA from patient blood samples.

Citation Format: Shuo Shen, Robert Brown, Daniel Kim, Larry Pastor, Andrew Y. Fu, Pushpinder Kaur, Alisha Babu, Wei Liu, Aiguo Zhang, Hiromi Tanaka, Michael Y. Sha. A novel XNA technology-based assay to detect JAK2 V617F mutation by real-time PCR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7295.
Abstract 730: Leveraging microdissection for proteogenomic analysis of histological sections to advance drug development
Authors: Shin Ik Jae , Tangrea Michael , Emmert-Buck Michael R. , Johann Donald J.
Published: March 2024

Background: Combining proteogenomics with laser capture microdissection (LCM) in cancer research offers a targeted way to explore the intricate interactions between tumor cells and the tumor microenvironment. This is especially important for immuno-oncology (IO) research where improvements in the predictability of patient response to IO-based drugs is sorely needed. An improved understanding of the spatial relationships involving tumor cells proper, stromal cells, blood supply and immune cell interactions may help to inform drug development and improve the indicators of success for IO-based drug regimens.

Methods: LCM is used to isolate and obtain distinct histological cell types from fresh frozen tissue. Once cells have been captured, nucleic acids and proteins are extracted for in-depth multi-modality molecular profiling assays involving multiple genomic modalities and a customized solution-based mass spectrometry proteomics approach for samples or specimens with a limited amount of tissue.

Results: Optimizing analysis of minute tissue quantities from LCM captured cells is challenging. Following the isolation of nucleic acids, RNA-seq may be performed for gene expression and DNA sequencing performed for the discovery and analysis of actionable mutations, copy number variation, and methylation profiles. Regarding genomic-based studies, commercial kits are often utilized for these steps due to their general availability, rapid innovation, and the robust performance of these products. However, this kit-based adaptive approach is not true for proteomics. There remains a need for highly sensitive proteomic methods targeting small-sized samples. A significant part of our proteogenomics approach is focused around an enhanced liquid chromatography mass spectrometry (LC-MS) analysis of micro-scale and/or nano-scale tissue sections. This is achieved with a silver-stained one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE) approach developed for LC-MS analysis of fresh-frozen tissue specimens obtained via LCM. This includes an in-gel digestion method adjusted and specifically designed to maximize the proteome coverage from amount-limited LCM samples to better facilitate in-depth molecular profiling.

Conclusions: Reported here is a proteogenomic approach that is leveraging from microdissected fresh frozen tissue. The methodology may also be applicable to other types of specimens having limited nucleic acids, protein quantity, and/or sample volume.

Citation Format: Ik Jae Shin, Michael Tangrea, Michael R. Emmert-Buck, Donald J. Johann. Leveraging microdissection for proteogenomic analysis of histological sections to advance drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 730.
Abstract 7300: Synergistic inhibition of prostate cancer growth by the combination of xanthohumol and ursolic acid
Authors: Clark Rachel , Saha Achinto , Friedman Chelsea A. , Gorgoglione Ruggiero , Tiziani Stefano , DiGiovanni John
Published: March 2024

Within the United States, prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer, and approximately 1 in 8 men will receive a diagnosis in their lifetime. As the second leading cause of cancer deaths in American men, about 1 in 41 will die because of prostate cancer. The World Health Organization has suggested that approximately one-third of all cancer deaths are preventable, and one of the suggested means of prevention is through the increased consumption of fruits and vegetables. Fruits and vegetables contain natural compounds known as phytochemicals which possess biological activity including some anti-cancer effects. By adapting the ATP-bioluminescence assay for cell viability, our laboratory screened a natural compound library to find combinations of these compounds that may synergistically inhibit PCa cell viability. One of the combinations to emerge from this screening process was xanthohumol (XAN) and ursolic acid (UA). We examined the ability of the combination to inhibit tumor growth in a mouse HMVP2 PCa allograft tumor model. Mice were fed diets supplemented with either XAN (0.2%) or UA (0.2%) alone or the combination. Mice on the combination diet showed a significant inhibition of HMVP2 PCa tumor growth compared to mice on the single-agent diets. In addition, in vitro studies were performed to support the allograft tumor study and to further examine the mechanism of action of the combination. A cell survival assay utilizing six different PCa cell lines indicated that the combination of XAN and UA synergistically inhibited the survival of all cell lines as calculated by the Bliss index. Mechanistic studies performed in PCa cells indicate that the combination of XAN and UA inhibits oncogenic signaling better than either agent alone. Additionally, unbiased metabolomics revealed that the tumors from mice fed the combination diet had significantly less S-adenosyl-L-methionine compared to all other groups. Overall, 13 metabolic pathways were significantly different in the tumors from mice fed the combination diet compared to all other groups. The current data suggest that using a combination of XAN and UA may be a valuable chemopreventive strategy for PCa in humans. Funding: This work was supported by NIH Grant CA228404.

Citation Format: Rachel Clark, Achinto Saha, Chelsea A. Friedman, Ruggiero Gorgoglione, Stefano Tiziani, John DiGiovanni. Synergistic inhibition of prostate cancer growth by the combination of xanthohumol and ursolic acid [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7300.
Abstract 7305: Chemoprevention of colorectal cancer: Role of trace minerals in conjunction with calcium
Authors: Harber Isabelle , McClintock Shannon , Varani James , Aslam Muhammad N.
Published: March 2024

Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. CRC usually develops from adenomas (CRC precursors) after a long latency period. Prevention is crucial in reducing CRC incidence and progression to cancer. Among several prevention options, calcium has been a widely considered chemo-preventative agent.

Aims: Calcium plays a vital role in the regulation of epithelial cell differentiation, which is essential for epithelial growth control. Epidemiological studies have demonstrated that adequate calcium intake is crucial for protection against colonic polyp formation and colorectal cancer. However, recent interventional trials with calcium have had only modest and mixed results, and the question is how to improve efficacy. One potential strategy is to use calcium in combination with additional minerals and trace elements.

Results: Our preclinical studies employing monolayer cultures with CRC cell lines and colon organoids cultures from colon polyps have shown that a calcium-rich mineral combination derived from fossilized red algae (Aquamin) is more effective than calcium alone in inducing differentiation, suppressing growth and upregulation of calcium-sensing receptor. When colonic adenomas in culture were subjected to differential proteomic analysis, Aquamin upregulated several proteins involved in proliferation suppression, DNA mismatch repair and inducing differentiation, and apoptosis. Two long-term mouse studies have demonstrated that Aquamin is more effective in suppressing polyp & CRC incidence compared to calcium alone. Based on these findings, we conducted a 90-day FDA-approved trial (a pilot study with ten subjects per arm) comparing the two interventions in human subjects at risk for CRC. Results showed that Aquamin treatment reduced proliferation and increased cell differentiation observed by immunohistochemistry. Proteomic analysis also revealed that the minerals upregulated several proteins related to growth suppression, inducing differentiation and those contributing to cell-cell and cell-matrix adhesion functions and downregulated proteins involved in proliferation and nucleic acid metabolism.

Conclusion: These results provide convincing evidence that a multi-mineral combination derived from red algae can provide benefits in preventing CRC that are not seen with calcium alone. Further studies, such as a polyp-prevention trial in human subjects, are warranted to advance these CRC prevention efforts.

Citation Format: Isabelle Harber, Shannon McClintock, James Varani, Muhammad N. Aslam. Chemoprevention of colorectal cancer: Role of trace minerals in conjunction with calcium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7305.
Abstract 7340: Investigating the function and impact of UBASH3B in head and neck squamous cell carcinoma and its implications for racial health disparities
Authors: Ndahayo Madeleine , Mukhina Vera , Gupta Ishita , Gaykalova Daria A.
Published: March 2024

Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the top cancers with significant cancer health disparities among racial and ethnic groups. African Americans (AAs) with HNSCC demonstrate worse overall survival compared to European Americans (EAs). While the reasons behind this disparity are multifaceted, recent findings suggest that biological features in HNSCC may contribute to differences in disease progression. However, race-related biological factors in HNSCC have been relatively little explored. We have identified the gene UBASH3B, a protein tyrosine phosphatase that plays a role in the stabilization of the Epidermal Growth Factor Receptor (EGFR). High expression of UBASH3B in AAs is associated with significantly worse overall survival compared to high expression in EAs and low expression in AAs. This study seeks to examine the role of UBASH3B in HNSCC and determine its impact on tumorigenesis. We hypothesize that the upregulation of UBASH3B in AAs contributes to the survival disparity by promoting tumor progression through EGFR signaling. Preliminary data using The Cancer Genome Atlas (TCGA) shows overexpression of UBASH3B in tumor samples of both AAs and EAs HNSCC samples. Plus, the overexpression of UBASH3B is associated with perineural invasion. Additionally, among AA-HNSCC patients, advanced T-stage is associated with increased UBASH3B expression. Elucidating the role UBASH3B plays in tumorigenesis will give us a further understanding of HNSCC in African Americans and can serve as a potential therapeutic target for new treatment options, as well as the biomarkers for the detection of the high-risk group.

Citation Format: Madeleine Ndahayo, Vera Mukhina, Ishita Gupta, Daria A. Gaykalova. Investigating the function and impact of UBASH3B in head and neck squamous cell carcinoma and its implications for racial health disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7340.
Abstract 7344: Role of ubiquitin receptor ADRM1 (Rpn13) in prostate cancer
Authors: Chowdhury Shahjalal , Wang Honghe , Nayak Chitra , Karanam Balasubramanyam
Published: March 2024

Adhesion-regulating molecule 1 (ADRM1)/Rpn13 is a component of the 19S regulatory subunit of the 26S proteasome [1]. ADRM1 plays a crucial role in the recognition of polyubiquitinated substrates of the proteasome and their subsequent deubiquitination and degradation [2]. ADRM1 transcript levels are commonly upregulated in diverse tumor types [3]. The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. In this study, we investigated the expression of ADRM1/Rpn13 in different stages of prostate cancer and its association with AR expression. TCGA data from UALCAN was used for understanding ADRM1 expression on different stages of diseases and single-cell RNA-sequencing data of prostate cancer cell line was obtained from Prostate Cancer Atlas. TCGA (cell, 2015) data set was used for investigating the correlation between ADRM1 and AR by using R programming. Our study from the TCGA dataset reveals that ADRM1 expression increased significantly with the aggressiveness of prostate cancer (increase consistently with the Gleason score) from the TCGA dataset. We analyzed ADRM1 and AR expression in different prostate cancer cell lines and obtained that ADRM1 expressed significantly higher in prostate cancer cell lines which had lower AR expression. TCGA (cell, 2015) dataset indicated a negative correlation between ADRM1 and AR expression in prostate cancer. Our preliminary analysis indicated that ADRM1 inhibitor might be a potential therapeutic option for AR-independent prostate cancer.

Citation Format: Shahjalal Chowdhury, Honghe Wang, Chitra Nayak, Balasubramanyam Karanam. Role of ubiquitin receptor ADRM1 (Rpn13) in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7344.
Abstract 7361: The prognostic value of TP53 and tumor suppressor gene mutations in temozolomide-treated IDH1 mutant low-grade glioma
Authors: Salem Yahia E. , Alragheb Bayan O. Abu
Published: March 2024

Background: Temozolomide has been extensively utilized in the treatment of gliomas across various grades, offering significant therapeutic benefits. However, the impact of concurrent mutations in TP53 and other tumor suppressor genes (TSG) on treatment outcomes in patients with IDH1 mutant low-grade glioma (LGG) treated with temozolomide remains to be fully understood. This study aims to explore the influence of these genetic factors on the response to temozolomide therapy, focusing on identifying potential genetic markers that can predict therapeutic outcomes.

Methods: Our study exclusively analyzed The Cancer Genome Atlas (TCGA) LGG PanCancer dataset from cBioPortal, focusing on IDH1 mutant cases treated with temozolomide. Data analysis was carried out using Python 3.11. The cohort was categorized based on genetic alterations: TP53 mutation with additional TSGs (ATRX, CIC, FUBP1, NOTCH1) mutations (TP53mut/TSGmut), TP53 mutation without additional TSG mutations (TP53mut/TSGwt), and no TP53 mutations (TP53wt).

Results: In our study, 178 LGG samples with IDH-1 mutation treated with temozolomide were selected. Of these, 113 samples had a mutation in TP53, and 88 had an additional mutation in a TSG. For TP53mut/TSGmut compared to TP53wt, the analysis revealed significant differences in clinical outcomes (PFS: HR 1.95, CI: 1.17-3.26, p=0.011; OS: HR 1.6, CI: 1.13-2.26, p=0.008). When comparing TP53mut/TSGwt with TP53mut/TSGmut, the findings were (PFS: HR 1.36, CI: 0.63-2.92, p=0.432; OS: HR 0.93, CI: 0.31-2.79, p=0.896). Finally, the comparison between TP53wt and TP53mut/TSGwt showed (PFS: HR 1.45, CI: 0.62-3.39, p=0.397; OS: HR 2.31, CI: 0.64-8.3, p=0.200).

Conclusion: The presence of concurrent mutations in TP53 and other TSGs in IDH1 mutant LGG patients (TP53mut/TSGmut) is indicative of a more aggressive disease course and reduced response to temozolomide treatment, as evidenced by significantly worse clinical outcomes. In contrast, the TP53mut/TSGwt group did not exhibit significant differences in treatment outcomes. These findings underscore the importance of detailed genetic profiling in developing personalized treatment strategies for this patient population.

Citation Format: Yahia E. Salem, Bayan O. Abu Alragheb. The prognostic value of TP53 and tumor suppressor gene mutations in temozolomide-treated IDH1 mutant low-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7361.
Abstract 7387: Fully automated segmentation and volumetric measurement of intracranial meningioma using deep learning
Authors: Kang Ho , Witanto Joseph N. , Pratama Kevin , Lee Doohee , Choi Kyu Sung , Choi Seung Hong , Kim Min-Sung , Kim Jin Wook , Kim Yong Hwy , Park Sang Joon , Park Chul-Kee
Published: March 2024

Most intracranial meningiomas are small, asymptomatic, and incidentally found tumors. Since the growth of meningioma is the principal indication of treatment, accurate and rapid measurement of the volume of intracranial meningiomas is essential in clinical practice to determine the growth rate of the tumor. It could be useful for the management of meningiomas given their increasing incidence and the wait-and-see policy currently in use for asymptomatic meningiomas. The aim of this study was to develop and validate a computational model for fully automated meningioma segmentation and volume measurement on contrast-enhanced MR scans using deep learning.

The retrospectively collected axial contrast-enhanced T1-weighted section images from patients diagnosed with meningioma were manually segmented and used to construct automatic segmentation models with six U-Net- and nnU-Net-based architectures. The performance of each model was evaluated with the Sørensen-Dice similarity coefficient (DSC) with internal (IVS) and external validation sets (EVS), each consisting of 100 independent MRI examinations.

A total of 12,909 section images from 459 patients were applied for the training (median age 58 [52-66] [IQR]; 385 women [83.9%]). The median tumor volume of the training set was 2.36 cm3. A 2D nnU-Net showed the highest median DSCs of 0.922 and 0.893 for the IVS and EVS, respectively. The nnU-Nets achieved superior performance in meningioma segmentation than the U-Nets. The DSCs of the 2D nnU-Net for small meningiomas less than 1 cm3 were 0.769 and 0.780 with the IVS and EVS, respectively.

We successfully developed a fully automated and accurate volumetric measurement tool for meningioma using nnU-Net. The volumetry performance for small meningioma was significantly better than that achieved in previous studies. The results of this study are clinically applicable and are expected to be of great use in the management of monitored meningioma patients.

Citation Format: Ho Kang, Joseph N. Witanto, Kevin Pratama, Doohee Lee, Kyu Sung Choi, Seung Hong Choi, Min-Sung Kim, Jin Wook Kim, Yong Hwy Kim, Sang Joon Park, Chul-Kee Park. Fully automated segmentation and volumetric measurement of intracranial meningioma using deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7387.
Abstract 7415: Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment
Authors: Vangara Raviteja , Diaz-Gay Marcos , Barnes Mark D. , Wang Xi , Islam S M Ashiqul , Vermes Ian , Duke Stephen , Narasimman Nithish Bharadhwaj , Yang Ting , Jiang Zichen , Moody Sarah , Senkin Sergey , Brennan Paul , Stratton Michael R. , Alexandrov Ludmil B.
Published: March 2024

Analysis of mutational signatures is a powerful approach for understanding the mutagenic processes that have shaped the evolution of a cancer genome. To evaluate the mutational signatures operative in a cancer genome, one first needs to quantify their activities by estimating the number of mutations imprinted by each signature, a process known as refitting of mutational signatures. Although multiple tools for refitting known signatures were developed in the past decade, most provide support almost exclusively for single base substitution signatures and lack an online interface. Further, these tools have never been compared, and no existing tool supports probabilistically assigning signatures to a single somatic mutation. Here, we present SigProfilerAssignment, a desktop and online computational framework for assigning all types of mutational signatures to individual samples. SigProfilerAssignment is the first tool that allows both analysis of copy-number signatures and probabilistic assignment of signatures to individual somatic mutations. As its computational engine, the tool uses a custom implementation of the forward stagewise algorithm for sparse regression and nonnegative least squares for numerical optimization. The analysis of 2,700 synthetic cancer genomes with and without noise demonstrates that SigProfilerAssignment outperforms four commonly used approaches for assigning mutational signatures, with consistent top performance across cancer types and most signatures. SigProfilerAssignment stands out as the most precise and sensitive tool while maintaining high computational performance and bringing novel capabilities. SigProfilerAssignment is distributed as an open-source Python/R package available at https://github.com/AlexandrovLab/SigProfilerAssignment, with an online interface available as part of the COSMIC Mutational Signatures website at https://cancer.sanger.ac.uk/signatures/assignment/.

Citation Format: Raviteja Vangara, Marcos Diaz-Gay, Mark D. Barnes, Xi Wang, S M Ashiqul Islam, Ian Vermes, Stephen Duke, Nithish Bharadhwaj Narasimman, Ting Yang, Zichen Jiang, Sarah Moody, Sergey Senkin, Paul Brennan, Michael R. Stratton, Ludmil B. Alexandrov. Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7415.
Abstract 7418: LongFuse: Detecting gene fusion transcripts from high throughput long-read single cell RNA sequencing data
Authors: Shiau Cheng-Kai , He Yueying , Lin Hsiao-Yun , Lu Lina , Lu Xiao-Dong , Yu Jindan , Gao Ruli
Published: March 2024

Gene fusion resulted from genomic translocation plays important oncogenic roles including but not limited to gene activation and changing protein coding sequences. Historically, fusion gene analysis has been limited to bulk levels resulting in mixed oncogene activation models. Single cell Nanopore RNA sequencing (scNanoRNAseq) has the unique strength in detecting full-length chimeric transcripts in thousands of single cells in parallel. However, robust computational tools for detecting fusion genes in single cells from scNanoRNAseq data are missing. Here, we developed LongFuse, a fast and accurate tool, to detect fusion genes and their splicing isoforms in single cells from scNanoRNAseq data. LongFuse implements an XOR logic gate algorithm to speed up fusion candidate searching and stringent criteria to eliminate false discoveries due to trans-splicing events and randomly ligated chimeras. We applied LongFUSE onto scNanoRNAseq data of both human prostate cancer cell line, VCaP, and tumor tissues with known TMPRSS2-ERG fusion. Our results showed that both cancer cell line and prostate tumors harbored a mixture of fusion positive and fusion negative tumor cells. Gene expression analysis revealed transcriptional differences between fusion positive and negative cells including genes involved in cancer cell proliferation and invasion programs such as ELL2, ZBTB16, IGF1R, ANK3, MYPOP and PLPP1 genes. LongFUSE also calculates the splicing isoforms of fusion gene transcripts, allowing prediction of protein sequences of fusion gene transcripts. Taken together, our data demonstrated that LongFUSE is a robust computational tool for detecting gene fusions and their splicing isoforms at single cell level from scNanoRNAseq data.

Citation Format: Cheng-Kai Shiau, Yueying He, Hsiao-Yun Lin, Lina Lu, Xiao-Dong Lu, Jindan Yu, Ruli Gao. LongFuse: Detecting gene fusion transcripts from high throughput long-read single cell RNA sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7418.
Abstract 7451: Translational models of ovarian cancer-associated cognitive impairment and chemotherapy-induced peripheral neuropathy
Authors: Lomeli Naomi , Argueta Donovan , Pearre Diana C. , Lepe Javier , Gupta Kalpna , Bota Daniela A.
Published: March 2024

Cisplatin is widely used to treat ovarian malignancies, and over 70% of ovarian cancer patients report experiencing cancer-related cognitive impairment (CRCI) and chemotherapy-induced peripheral neuropathy (CIPN) during and after chemotherapy treatment. Most pre-clinical CRCI/CIPN studies have been conducted on non-tumor bearing rodents. We developed two novel clinically relevant models of CRCI/CIPN: (1) the ID8 syngeneic mouse model in B6(Cg)-Tyrc-2J/J female mice, and (2) the SKOV3.ip1 ovarian cancer xenograft model in female Cr:NIH-RNU rats. We examined cognitive function and serum cytokine levels with respect to cancer progression and/or in response to cisplatin. B6 female mice were injected with 107 ID8 cells or 0.9% saline, i.p. Mice received cisplatin (2.3 mg/kg/day, i.p.) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) for 5d, followed by 5d of rest for two cycles. RNU rats were injected with 107 SKOV3.ip1 cells or 0.9% saline, i.p. Rats received cisplatin (5 mg/kg, i.p) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) every other week for four cycles. OvT+CIS and OvT+VEH mice and rats showed impairments in novel object recognition (NOR), with discrimination ratios ≤0.5. Cisplatin transiently increased hyperalgesia in OvT+CIS mice, which persisted longitudinally in OvT+VEH mice. Serum cytokine levels were elevated in OvT+VEH mice (IL-2, IL-10, INFγ) and OvT+VEH rats (IL-4, IL-10) compared to OvT+CIS (P<0.05). Ovarian cancer may evoke progressive sensory and neurocognitive deficits and increase systemic pro-inflammatory cytokine levels in the absence of chemotherapy. Future studies will address hyperalgesia and cognitive differences between healthy control and ovarian cancer models +/- cisplatin, and biological mechanisms underlying CRCI and CIPN.

Citation Format: Naomi Lomeli, Donovan Argueta, Diana C. Pearre, Javier Lepe, Kalpna Gupta, Daniela A. Bota. Translational models of ovarian cancer-associated cognitive impairment and chemotherapy-induced peripheral neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7451.