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  • American Association for Cancer Research (AACR)  (7)
  • 1
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    Abstract A042: Keratin 17 is a negative prognostic and predictive biomarker in pancreatic ductal adenocarcinoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 22_Supplement ( 2022-11-15), p. A042-A042
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 22_Supplement ( 2022-11-15), p. A042-A042
    Abstract: Background: There is an urgent need to understand why patients with clinically and histologically identical pancreatic ductal adenocarcinomas (PDACs) differ in response to treatment, disease progression, and survival. Although two standard chemotherapies are available, predictive biomarkers to guide regimen selection have not been defined. We previously reported that keratin 17 (K17) expression is a hallmark of PDAC cases with shortest patient survival. Furthermore, K17, explored using in vitro and in vivo murine models, drives resistance to gemcitabine and 5-fluorouracil, the most common chemotherapeutic agents in the two chemotherapies. Here, we aimed to validate the prognostic value of K17 and to further explore its role as a predictive biomarker. Methods: We used a cohort of 305 cases, with localized disease and who had gone tumor resection. An indirect immunoperoxidase method was used to detect K17 expression on surgical specimens, as previously described. Survival was plotted using the Kaplan–Meier method and hazard ratios (HRs) were calculated using Cox proportional hazard regressions for both, overall survival (OS) and progression-free survival (PFS). Results: Patients in the high-K17 expression group had shorter overall survival [median=25 mo., HR=1.511, p=0.0338] than those in the low-K17 expression group (median=42 mo.). In addition, high K17 expression was associated with shorter median OS (p=0.0280) and PFS (p=0.0434) in patients who were treated with gemcitabine (GEM) or with Gemcitabine/nab-Paclitaxel (GEMTAX) therapy (OS p=0.1959, PFS p=0.0724), compared to low-K17 counterparts. When we further separated our cohort by K17 level of expression and compared GEM and GEMTAX responses, we found that patients with tumors with high K17 expression do not benefit from GEMTAX adjuvant therapy (p=0.0356). Of note, K17 expression within the responder group was significantly lower than in tumors within the non-responder group for both Gem and GEMTAX (p & lt;0.001). Conclusions: K17 expression is confirmed as a robust prognostic biomarker, significantly correlated with poor OS and PFS in two independent cohorts of PDAC patients. More importantly, our results indicate that K17 expression predicts PDAC resistance to gemcitabine and poor response to GEMTAX. Collectively, our findings have implications could guide the development of K17 as a predictive biomarker for gemcitabine-based interventions in both adjuvant and palliative settings, to optimize therapeutic efficacy for PDAC. Citation Format: Lyanne Oblein, Lucia Roa-Peña, Sruthi Babu, Felicia D. Allard, Natalia D. Marchenko, Luisa F. Escobar-Hoyos, Kenneth R. Shroyer. Keratin 17 is a negative prognostic and predictive biomarker in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A042.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA22-A042
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    Abstract B50: Keratin 17 drives tumor aggression and could be targeted for treatment of pancreatic ductal adenocarcinoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 24_Supplement ( 2019-12-15), p. B50-B50
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 24_Supplement ( 2019-12-15), p. B50-B50
    Abstract: Our aims are to uncover the molecular mechanisms through which keratin 17 (K17), a prognostic biomarker, drives tumor aggression and to target these mechanisms to provide more effective treatment for pancreatic ductal adenocarcinoma (PDAC). In murine orthotopic xenografts, we found that K17-positve PDACs survive for a shorter interval than controls. Prompted by previous reports that post-translational modifications (PTMs) regulate intermediate filament dynamics, we established in vitro that phosphorylated K17 detaches from the cytoskeleton and enters the nucleus, where it promotes tumor growth by targeting tumor suppressor proteins, including p27, for nuclear export and degradation. To further understand the events that control K17 solubilization, we sequenced K17 from primary PDACs by liquid chromatography-mass spectrometry and identified serine sites within the N-terminus that are phosphorylated only in soluble K17. Furthermore, phosphorylation is required to maintain K17 solubility and soluble K17 accumulates in the nucleus of PDAC cells. By an unbiased screen of 80 small-molecule kinase inhibitors in PDAC, we determined that SYK kinase inhibitors, already in clinical trials for other malignancies, abrogated K17 solubilization. Prompted by our finding that K17 serves as a nuclear shuttle of p27, we identified two amino acid sequences in K17 that have similar polarity to sequences that are used by cyclins to dock to p27. Point mutations in two of these domain key residues blocked K17-mediated degradation of nuclear p27, and we identified similar effects in the background of wild-type and oncogenic KrasG12D PDAC cells. Current studies are under way to find additional protein and RNA targets for potential therapeutic intervention. Using patient-derived organoids, human and murine PDAC cells, we determined that K17-expressing PDAC cells are more than twice as resistant as isogenic K17-negative cells to gemcitabine (Gem) and 5-fluorouracil (5-FU), two key components of current chemotherapeutic regimens. By unbiased liquid chromatography-coupled tandem mass spectrometry metabolomics, RNA-sequencing analyses (TCGA), and in vivo magnetic resonance spectroscopy, we found that K17 induces metabolic reprogramming by increasing glycolysis and pyrimidine biosynthesis, pathways that have been linked to chemoresistance. We are extending this work to determine if disruption of K17-mediated metabolic rewiring by small-molecule inhibitors will resensitize tumor cells to pyrimidine analogues. In conclusion, K17 undergoes key post-translational modifications that enable solubilization and nuclear translocation, the targeting of tumor suppressor proteins, and enhanced pyrimidine biosynthesis to drive chemoresistance. Uncovering these mechanisms could ultimately lead to the identification of novel approaches to target the oncogenic functions of K17, and thereby, to enable the development of more effective treatment options for PDAC. Citation Format: Kenneth R. Shroyer, Luisa Escobar-Hoyos, Cindy Leiton, Chun-Hao Pan, Ryan Kawalerski, Lucia Roa-Peña, Sruthi Babu. Keratin 17 drives tumor aggression and could be targeted for treatment of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B50.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA19-B50
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 3
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    Abstract PO-040: Therapeutic targeting of keratin 17 functional domains and nuclear export uncover therapeutic vulnerabilities of pancreatic cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 22_Supplement ( 2020-11-15), p. PO-040-PO-040
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 22_Supplement ( 2020-11-15), p. PO-040-PO-040
    Abstract: The purpose of this study is to launch a novel biomarker-based targeted therapy that may result in improved precision and efficacy for the treatment of pancreatic ductal adenocarcinoma (PDAC). We discovered that Keratin 17 (K17), an oncofetal intermediate filament and nuclear oncoprotein expressed in 50% of PDAC cases, is a biomarker of the most aggressive and treatment-resistant form of PDAC. We set out to validate K17 as a druggable target and to identify K17-targeting mechanisms. In pre-clinical mouse models, animals bearing K17+ PDACs display the shortest survival, suggesting that K17 drives tumor aggression and should be explored as a potential therapeutic target. We used the following two approaches aimed to inhibit K17 nuclear shuttle functions, in order to identify therapeutic strategies: 1) Targeting K17 functional domains: By protein-sequence modeling analyses and site-directed mutagenesis, we identified functional domains in K17 (K17-FDs) that bind to, shift the subcellular localization of, and promote the degradation of nuclear tumor suppressors (e.g. p27). Using SILAC mass spectrometry of nuclear proteomes from isogenic human cells, we found that 80% of the nuclear proteome is altered by K17, that half of these proteins encode the domain targeted by the K17-FDs, and that a large proportion of these proteins are involved in gene expression. Animals harboring tumors with mutated K17-FDs lived two-times longer than control animals bearing K17+ PDACs, suggesting that the K17-FDs may be therapeutic targets. We are currently testing small molecule and peptide inhibitors to target the K17-FDs in vitro and in vivo, as a discovery approach to design small-molecule inhibitors of K17. 2) Targeting K17 nuclear export: K17 impacts the nuclear export of ~50% of the proteome and depends on exportin-1 (XPO1). We found that K17+ PDAC cells were more sensitive to Selective Inhibitor of Nuclear Export (SINE) therapy, leading to a 2-fold increase in cell death compared to control cells, suggesting that nuclear export by K17 in PDAC cells could be therapeutically targeted. SINE therapy is currently FDA-approved for treatment of other cancer types and repurposing for the treatment of K17-positive PDACs may result in enhanced therapeutic efficacy. In conclusion, these studies provide the basis for the development of novel biomarker-based therapeutic approaches using small-molecule inhibitors, to target K17 active sites or the pathways altered by this protein in PDAC. Citation Format: Cindy V. Leiton, Chun-Hao Pan, Ji Dong Bai, Lucia Roa-Peña, Sruthi Babu, Alex Penson, Nashaat Turkman, Richard Moffitt, Markus Seeliger, David Talmage, Kenneth R. Shroyer, Luisa F. Escobar-Hoyos. Therapeutic targeting of keratin 17 functional domains and nuclear export uncover therapeutic vulnerabilities of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-040.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA20-PO-040
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
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    Abstract B01: Validation of a novel cytologic biomarker for urothelial carcinoma
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 15_Supplement ( 2020-08-01), p. B01-B01
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 15_Supplement ( 2020-08-01), p. B01-B01
    Abstract: Introduction: Cytology and cystoscopy have limited sensitivity and specificity for the diagnosis of urothelial carcinoma (UC), due to inflammatory atypia, sampling errors, and other clinicopathologic factors that may obscure test results. Therefore, there remains a clinical need to identify biomarkers to improve the diagnostic accuracy to detect UC. Keratin 17 (K17) is an embryologic cytokeratin that functions as an oncoprotein to promote the degradation of tumor suppressors that drive tumorigenesis. Published work from our group established that K17 is highly expressed in UC and confirmed specificity for UC by immunohistochemical localization of K17 in tissue biopsies of both low-grade and high-grade UCs (Babu et al., Mod Pathol, 2018). Objective: The objective of the current study was to develop an immunocytochemical (ICC) assay to determine K17 is a sensitive and specific biomarker to enhance diagnostic accuracy for UC in urine cytology. Methods: 80 ThinPrep CytoLyt-fixed urine specimens, collected at Stony Brook Medicine in 2018, including 39 with a clinicopathologic diagnosis of UC based on current cytologic diagnosis, and/or a history of biopsy confirmed UC within one year (+/-) of urine cytology specimen collection. K17 ICC was performed by indirect immunoperoxidase methods and K17 test results were scored based on the detection of immunoreactive urothelial cells and not on an assessment of cytologic atypia. The sensitivity and specificity of urine K17 ICC for detection of urothelial neoplasia was calculated by comparison of ICC test results with the cytologic diagnosis and/or the histologic diagnosis of positive cystoscopic biopsy specimens (papillary urothelial neoplasm of low malignant potential [PUNLMP, n=1] or greater). Samples that had no history of abnormal urine cytologic or biopsy diagnosis were categorized as negative for urothelial neoplasia. Results: Relative to the final clinicopathologic diagnosis of UC (n=38) or PUNLMP (n=1), K17 ICC had a sensitivity of 100% (95% CI: 91-100%) and specificity of 90% (95% CI: 77-96%). The positive predictive value was 90% (95% Cl: 78-96%) and the negative predictive value was 100% (95% Cl: 90-100%). Comparing ICC test results to cytologic and biopsy diagnoses, K17 ICC was positive in 9/23 (39%) cases with negative urine cytology. Of these 9 cases, 4 cases had biopsy confirmed UC. K17 ICC was positive in 4/11 (36%) of cases with inflammatory/reactive changes. Of these 4 cases, 3 had biopsy-confirmed UC. K17 ICC was positive in 14/30 (46%) of cases with mild atypia. Of these 14 cases, 12 had biopsy-confirmed UC and 1 had PUNLMP. K17 ICC was positive in 16/16 (100%) of cases with moderate atypia (n=8), severe atypia (n=3), or UC (n=5), all with biopsy-confirmed UC. Conclusions: K17 ICC is a novel and highly sensitive and specific diagnostic test for underlying biopsy-confirmed UC among samples with inflammatory/reactive changes, cytologic atypia, or positive urine cytology. Thus, the K17 test could serve as an adjunct to guide the clinical management of UC cases. Citation Format: Sruthi Babu, Lucia Roa-Peña, Ina Chan, Nam W. Kim, Sholeh Jahanfard, Luisa F. Escobar-Hoyos, Kenneth R. Shroyer. Validation of a novel cytologic biomarker for urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B01.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.BLADDER19-B01
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
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    Abstract C071: Keratin 17 excludes CD8-positive T cells and recruits CD163-positive macrophages in pancreatic ductal adenocarcinoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 22_Supplement ( 2022-11-15), p. C071-C071
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 22_Supplement ( 2022-11-15), p. C071-C071
    Abstract: Background: Keratin 17 (K17) is a negative prognostic biomarker, overexpressed in the biologically most aggressive forms of pancreatic ductal adenocarcinoma (PDAC). In other anatomic sites and disease processes, K17 expression also correlates with immune cell infiltrates and could block T-cell infiltration. Thus, we hypothesized that K17 expression correlates with the inflammatory microenvironment in PDAC. In this study, we aimed to determine the relationship between the stromal immune cell infiltrates and K17 expression, using multiplexed immunohistochemistry (mIHC) and our suite of deep learning tools to quantitatively evaluate the expression of four biomarkers of T-cells and macrophages in PDAC. Methods: mIHC was performed on representative sections of 201 primary PDACs from Stony Brook University Hospital, Thomas Jefferson University Hospital, Cedars Sinai Medical Center, and from a national cohort (KYT, Pancreatic Cancer Action Network, and Perthera). Antibodies for CD4 (helper T-cells), CD8 (cytotoxic T-cells), CD16 (pan-macrophage), CD163 (M2 macrophages), pancytokeratin, and K17 were provided by Roche Diagnostics Corporation through a sponsored research agreement. mIHC was performed on a Discovery Ultra Autostainer (Roche), using horseradish peroxidase (HRP) and alkaline phosphatase (AP)-based protocols with multiple chromogens (Red: CD4, Purple: CD8, Yellow: CD16, Green: CD163, Teal: pancytokeratin, and Brown: K17) to enable multispectral imaging of diverse immune cell populations within the cancer microenvironment. A deep learning analysis workflow was used to detect and classify stromal inflammatory cells, in whole slide images (WSIs), generated using an Olympus VS120 digital microscope (Olympus, Tokyo, Japan). Pixel-wise predictions from a color auto-encoder (ColorAE) union UNET anchor UNET model were combined to create multi-class masks that were further analyzed to perform detection and classification. Results: The analysis of the inflammatory microenvironment focused on defining immune cell infiltrates located within 25 microns of the closest K17-positive versus K17-negative tumor cell in each representative section. Across the sum of K17-positive and negative zones/section, CD4 cell counts ranged from 0-10,617 (mean 2,709), CD8 cell counts ranged from 63-28,596 (mean 6,745), CD16 cell counts ranged from 4-7,797 (mean 3,024), and CD163 cell counts ranged from 35-34,696 (mean 14,968). CD4 T-helper cells, CD8 cytotoxic T cells, and CD16 macrophages were more numerous (respectively, p=0.0012; p= & lt;0.0001; p= & lt;0.0001) in K17-negative tumor zones compared to K17-positive zones. By contrast, the number of CD163 (M2) tumor-promoting macrophages was greater in K17 positive zones (p=0.0019). Conclusion: K17 expression by tumor cells impacts the chronic inflammatory microenvironment, shielding tumor cells from immune cell mediated cytotoxic responses, while recruiting tumor-promoting M2 macrophages, indicating that K17 impacts the immune response as a fundamental hallmark of aggression in PDAC. Citation Format: Lyanne Oblein, Michael Horowitz, Mahmudul Hasan, Sruthi Babu, Mariana Torrente-Goncalves, Lucia Roa, Jaymie Oentoro, Jason Harper, Xin Yao Zheng, Wei Jiang, Andrew Hendifar, Natalie Moshayedi, Brent Larson, Veronica Placencio-Hickok, Edik Blais, Emmanuel Petricoin, Joel Saltz, Natalia D. Marchenko, Luisa F. Escobar-Hoyos, Kenneth Shroyer. Keratin 17 excludes CD8-positive T cells and recruits CD163-positive macrophages in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C071.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA22-C071
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Abstract C32: Therapeutic targeting of keratin 17 and nuclear export uncover therapeutic vulnerabilities of pancreatic cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 24_Supplement ( 2019-12-15), p. C32-C32
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 24_Supplement ( 2019-12-15), p. C32-C32
    Abstract: The purpose of this study is to launch a novel biomarker-based targeted therapy that may result in improved precision and personalized medicine for pancreatic ductal adenocarcinoma (PDAC). We discovered that keratin 17 (K17), an intermediate filament (IF), is a nuclear oncoprotein found in 50% of PDAC cases, identifying the most aggressive and treatment-resistant form of PDAC and functioning as a biomarker. We set out to validate K17 as a druggable target and to identify K17-targeting mechanisms. In preclinical mouse models, animals bearing K17-expressing PDACs display the shortest survival interval, suggesting that K17 drives tumor aggression and is a potential therapeutic target. We used the following two approaches aimed to inhibit K17 nuclear shuttle functions in order to identify potential therapeutic strategies. 1) Targeting K17 functional domains: By protein-sequence modeling analyses and site-directed mutagenesis, we identified functional domains in K17 (K17-FDs) that bind to, shift the subcellular localization of, and promote the degradation of nuclear tumor suppressors (i.e., p27). Using SILAC mass spectrometry analysis of nuclear proteomes from isogenic human cells, we found that 80% of the nuclear proteome is altered by K17, that half of these proteins encode the domain targeted by the K17-FDs, and that a large proportion of these proteins are involved in gene expression. Animals harboring tumors with mutated K17-FDs lived two times longer than control animals, suggesting that the K17-FDs may be therapeutic targets. We are currently testing small-molecule and peptide inhibitors to target the K17-FDs in vitro and in vivo, as a discovery approach to design small-molecule inhibitors of K17. 2) Targeting K17 nuclear export: K17 impacts the export of ~50% of the proteome and depends on exportin-1 (XPO1) for nuclear export. We found that PDAC cells expressing K17 were more sensitive to Selective Inhibitor of Nuclear Export (SINE) therapy, leading to a 2-fold increase in cell death compared to control cells, suggesting that nuclear export is a necessary oncogenic pathway exploited by K17 in PDAC cells. SINE therapy is currently FDA approved for treatment of other cancer types, and repurposing for the treatment of K17-positive PDACs may result in enhanced therapeutic efficacy. In conclusion, these studies provide the basis for novel biomarker-based therapeutic approaches for the most aggressive PDAC cases using small-molecule inhibitors that directly target K17 active sites or the pathways altered by this protein. Citation Format: Cindy V. Leiton, Chun-Hao Pan, Ji Dong Bai, Lucia Roa-Peña, Sruthi Babu, Alex Penson, Nashaat Turkman, Richard Moffitt, Markus Seeliger, David Talmage, Kenneth R. Shroyer, Luisa F. Escobar-Hoyos. Therapeutic targeting of keratin 17 and nuclear export uncover therapeutic vulnerabilities of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C32.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA19-C32
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Abstract PO-023: Targeting a novel rewired pathway of nucleotide metabolism that drives chemoresistance in the most lethal molecular subtype of pancreatic cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 22_Supplement ( 2020-11-15), p. PO-023-PO-023
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 22_Supplement ( 2020-11-15), p. PO-023-PO-023
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) includes two molecular subtypes, of which the basal-like subtype is associated with the shortest survival and is highly resistant to chemotherapy. The basal-like subtype is defined by a 25-gene signature; however, the role of these genes in promoting tumor aggression remains unexplored. Here, we set out to uncover the mechanisms of chemoresistance and explore targeted therapies for this subtype. We focused on studying an oncofetal antigen, keratin 17 (K17), which is the most overexpressed hallmark gene of the basal-like PDAC. We manipulated the expression of K17 and found that in multiple in vitro and in vivo models of PDAC, spanning human and murine PDAC cells and orthotopic xenografts, K17 expression resulted in a greater than two-fold increase in resistance to Gemcitabine (Gem) and 5-fluorouracil, the major chemotherapeutic agents in standard-of-care treatments. To uncover the mechanisms associated with K17-induced chemoresistance, we performed unbiased metabolomic studies in isogenic PDAC cell lines and found that compared to control cells, K17 increases intracellular levels of deoxycytidine (dC) by four-fold that promote Gem (dC analogue) resistance. Based on previous findings that K17 enters nucleus to regulate gene expression, we explored whether K17 triggers metabolic reprogramming at the transcriptional level and found that enzymes involved in pyrimidine biosynthesis are positively correlated with K17 expression in PDAC cells. Given that it is still poorly understood how K17 regulates gene expression, we performed domain-prediction analyses. We discovered and validated a novel chromatin remodeling domain on K17 that is required for metabolic reprogramming. We are now performing ChIP-Seq and RNA-Seq to understand how this domain alters pyrimidine biosynthesis. To identify small molecules that could target K17-expressing PDACs potentially by disrupting metabolic reprograming, we performed an unbiased high-throughput drug screen and found that Podophyllotoxin (PPT), a microtubule inhibitor, significantly and selectively killed K17-positive compared to K17-negative PDAC cells. In the clinic, another microtubule inhibitor, Paclitaxel (PTX), is used in combination with Gem as a first line chemotherapy. Surprisingly, when combined with Gem, PPT but not PTX, was synergistic in inhibiting the viability of K17-expressing PDAC cells and enhanced survival of mice bearing K17-expressing PDACs. Currently, we are exploring the role of PPT in regulating pyrimidine biosynthesis. In summary, we identified a novel pathway of chemoresistance and a compound that could result in developing a biomarker-based personalized therapy. Citation Format: Chun-Hao Pan, Yuka Otsuka, BanuPriya Sridharan, Melissa Woo, Cindy V. Leiton, Sruthi Babu, Mariana Torrente Gonçalves, Ryan R. Kawalerski, Ji Dong K. Bai, Richard A. Moffitt, Jiang Zhao, David K. Chang, Andrew V. Biankin, Tim Duong, Pankaj K. Singh, Louis Scampavia, Timothy Spicer, Kenneth R. Shroyer, Luisa F. Escobar-Hoyos. Targeting a novel rewired pathway of nucleotide metabolism that drives chemoresistance in the most lethal molecular subtype of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-023.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA20-PO-023
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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