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  • American Association for Cancer Research (AACR)  (10)
  • 1
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    Abstract 4150: Blockade of CXCR2 mediated granulocytic MDSC recruitment synergizes with CCR2 inhibition of inflammatory monocytes and restores anti-tumor immunity in pancreatic adenocarcinoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4150-4150
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4150-4150
    Abstract: Introduction: Pancreatic cancer (PC) is characterized by a dense tumor stroma with a heavy leukocytic infiltrate, comprised predominately of immunosuppressive bone marrow (BM) derived cells. We have previously demonstrated in a phase Ib clinical trial that CCR2 inhibition (CCR2i) prevents inflammatory monocyte (IM) recruitment from the BM and results in a significant reduction of tumor associated macrophages (TAM) and an increase in treatment efficacy. However, granulocytic myeloid derived suppressor cells (G-MDSC) remain in the tumor microenvironment (TME) following CCR2i. Herein, we explored the impact of targeting G-MDSC recruitment to PC tumors both alone and in combination with CCR2i. Methods: Human BM, blood, and tumor was collected under an IRB approved protocol. A tissue microarray (TMA) from resected PC patients was analyzed for immune infiltrate. Mice were injected orthotopically with 2.5×106 syngeneic PC cells. CXCR2 and CCR2 inhibitors (Tocris) were given twice daily. Tumor growth was assessed and specimens obtained for analysis by flow cytometry, RNAseq, and IHC. Results: Human PC overexpresses CXCL5 and CXCL8, corresponding with an abundance of tumor infiltrating CXCR2+ G-MDSC. Furthermore, the ratio of CD8 to G-MDSC correlates with survival in human PC patients. In an orthotopic murine model that recapitulates human disease, ΣCXCL ligands were also increased. Either Ly6G depletion or targeted blockade with a CXCR2 inhibitor decreased G-MDSC and reduced tumor burden. Intriguingly, blockade of IM from the BM did not reduce G-MDSC and paradoxically resulted in a modest increase in this population within the tumors from human patients following CCR2i. Thus, we explored the combination of CCR2/CXCR2 blockade both with and without FOLFIRINOX chemotherapy. This resulted in a synergistic impact when both BM derived populations were targeted and dual therapy was further enhanced by FOLFIRINOX. RNAseq analysis of tumors following monotherapy or dual inhibition revealed alterations in the TME favoring an anti-tumor immune response. To test the hypothesis that this effect was mediated by restoration of anti-tumor immunity we analyzed the tumor infiltrating lymphocyte (TIL) populations and found a significant increase in the relative and absolute numbers of CD8+ and C4+ TIL. Analysis of the activation status of these cells demonstrated an increase in effector CD8+ T-cell phenotype (IFNγ+, CD69+, CD44+). Using Nur77GFP T-cell receptor reporter mice, we showed an increase in GFP expressing CD8+ TIL following dual blockade. CD8 depletion resulted in a loss of therapeutic efficacy of myeloid blockade, further confirming our hypothesis. Conclusion: These findings suggest that combinatorial blockade strategies preventing tumor infiltration by myeloid cells may restore anti-tumor immunity in PC. Citation Format: Timothy M. Nywening, Brian A. Belt, Roheena Z. Panni, Darren Cullinan, Dominic E. Sanford, Ryan C. Fields, William G. Hawkins, David G. DeNardo, William E. Gillanders, Peter Goedegebuure, David C. Linehan. Blockade of CXCR2 mediated granulocytic MDSC recruitment synergizes with CCR2 inhibition of inflammatory monocytes and restores anti-tumor immunity in pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4150.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-4150
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 2
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    Targeting Tumor-Infiltrating Macrophages Decreases Tumor-Initiating Cells, Relieves Immunosuppression, and Improves Chemotherapeutic Responses
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 3 ( 2013-02-01), p. 1128-1141
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 3 ( 2013-02-01), p. 1128-1141
    Abstract: Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination, and the induction of immune suppression. Cancer stem cells are far from a static cell population; rather, their presence seems to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact immune responses have on tumor stem cell differentiation or expansion is not well understood. In this study, we show that targeting tumor-infiltrating macrophages (TAM) and inflammatory monocytes by inhibiting either the myeloid cell receptors colony-stimulating factor-1 receptor (CSF1R) or chemokine (C–C motif) receptor 2 (CCR2) decreases the number of tumor-initiating cells (TIC) in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses. Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3, thereby facilitating macrophage-mediated suppression of CD8+ T lymphocytes. Together, our findings show how targeting TAMs can effectively overcome therapeutic resistance mediated by TICs. Cancer Res; 73(3); 1128–41. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-2731
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 3
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    Inflammatory Monocyte Mobilization Decreases Patient Survival in Pancreatic Cancer: A Role for Targeting the CCL2/CCR2 Axis
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 13 ( 2013-07-01), p. 3404-3415
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 13 ( 2013-07-01), p. 3404-3415
    Abstract: Purpose: To determine the role of the CCL2/CCR2 axis and inflammatory monocytes (CCR2+/CD14+) as immunotherapeutic targets in the treatment of pancreatic cancer. Experimental Design: Survival analysis was conducted to determine if the prevalence of preoperative blood monocytes correlates with survival in patients with pancreatic cancer following tumor resection. Inflammatory monocyte prevalence in the blood and bone marrow of patients with pancreatic cancer and controls was compared. The immunosuppressive properties of inflammatory monocytes and macrophages in the blood and tumors, respectively, of patients with pancreatic cancer were assessed. CCL2 expression by human pancreatic cancer tumors was compared with normal pancreas. A novel CCR2 inhibitor (PF-04136309) was tested in an orthotopic model of murine pancreatic cancer. Results: Monocyte prevalence in the peripheral blood correlates inversely with survival, and low monocyte prevalence is an independent predictor of increased survival in patients with pancreatic cancer with resected tumors. Inflammatory monocytes are increased in the blood and decreased in the bone marrow of patients with pancreatic cancer compared with controls. An increased ratio of inflammatory monocytes in the blood versus the bone marrow is a novel predictor of decreased patient survival following tumor resection. Human pancreatic cancer produces CCL2, and immunosuppressive CCR2+ macrophages infiltrate these tumors. Patients with tumors that exhibit high CCL2 expression/low CD8 T-cell infiltrate have significantly decreased survival. In mice, CCR2 blockade depletes inflammatory monocytes and macrophages from the primary tumor and premetastatic liver resulting in enhanced antitumor immunity, decreased tumor growth, and reduced metastasis. Conclusions: Inflammatory monocyte recruitment is critical to pancreatic cancer progression, and targeting CCR2 may be an effective immunotherapeutic strategy in this disease. Clin Cancer Res; 19(13); 3404–15. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-0525
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 4
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    Abstract A64: Peripheral blood monocytes predict survival in pancreatic cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 1_Supplement ( 2013-01-01), p. A64-A64
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 1_Supplement ( 2013-01-01), p. A64-A64
    Abstract: Background: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with a 5-year survival of & lt; 5%, and a mortality rate nearly equal to its incidence. Characteristic of this tumor is a microenvironment in which monocytes/macrophages are abundant. Human monocytes are divided into two major subsets: inflammatory (IM) and resident (RM) monocytes. IM make up 85%-90% of human peripheral blood monocytes, and are identified by the expression of CD14 and CCR2. The CCL2-CCR2 chemokine axis is a crucial signaling pathway in physiologic IM recruitment from the bone marrow under inflammatory conditions. Within the tumor microenvironment, IM can differentiate into tumor associated-macrophages (TAM) which are immunosuppressive, and directly promote tumor progression by enhancing angiogenesis, growth, and invasion. We present evidence that IM are recruited from the bone marrow to the peripheral blood and tumors of PDAC patients. Furthermore, we hypothesize that that peripheral blood monocyte count is predictive of patient survival in PDAC. Methods: PDAC tumor specimens (n=11) and normal pancreas (n=10) were subjected to flow cytometry and RT-PCR. Flow cytometry was performed on the peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) of PDAC patients (n=13) and compared to healthy controls (n=11). For the survival analysis, 483 patients with PDAC underwent pancreaticoduodenectomy between 1997 and 2011 at a single institution. We excluded 110 patients with pre-operative leukocytosis (WBC & gt;11,000 cell/ul) or who died within 30 days of surgery. We stratified the remaining 373 patients into 3 groups based on the prevalence of monocytes in peripheral blood leukocytes using their pre-operative CBC: low( & lt;6%)[n=47], mid(≥6% to & lt;11%)[n=271], and high(≥11%)[n=55] %monocyte groups. We used standard Kaplan-Meier survival statistics to compare overall survival between the three groups. Results: PDAC tumors are infiltrated by CCR2+ cells of monocyte lineage (CD45+, CD11b+, HLA-DR+, CD115+, CD14+) [37.9% ±1.6% of CD45+ cells], and these tumors expressed significantly more CCL2 relative to normal pancreas[p & lt;0.01]. IM (CD45+, CD11b+, HLA-DR+, CD14+, CCR2+, CD16-, CX3CR1 low) were significantly more prevalent in the PBMC of PDAC patients compared to controls [10.8%±1.1% vs 5.7%±1.1% of CD45+ cells; p & lt;0.005]; whereas, resident monocytes (CD45+, CD11b+, HLA-DR+, CD16+, CX3CR1 high, CD14 low, CCR2-) were not significantly different [0.67% ±0.1% vs 0.72% ±0.1%; p=0.76] . However, IM were significantly decreased in the bone marrow of PDAC patients compared to healthy controls [10.4% ±1.1 vs 14.9 ±1.2%; p & lt;0.01]. This suggests that the mechanism of increased IM in the peripheral blood of PDAC patients is mobilization from the bone marrow. Survival analysis of PDAC patients revealed that patients in the low %monocyte group survived significantly longer than patients in the high %monocyte group (27.8 months vs 18.2 months; p=0.02 on log-rank test). Also, there was a statistically significant incremental decrease in survival from the low to mid to high %monocyte groups (p=0.01 on log-rank test for trend). Conclusion: IM are recruited from the bone marrow to the tumor microenvironment in PDAC through the CCL2/CCR2 chemokine axis, and the prevalence of peripheral blood monocytes correlates with decreased patient survival. Developing effective intervention strategies to thwart monocyte recruitment may hold significant promise in this disease. Citation Format: Dominic E. Sanford, Brian A. Belt, Roheena Z. Panni, Jonathan B. Mitchem, David G. Denardo, S. Peter Goedegebuure, David C. Linehan. Peripheral blood monocytes predict survival in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A64.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TUMIMM2012-A64
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 5
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    Abstract B83: Targeting tumor-infiltrating macrophages decreases pancreatic tumor-initiating cells and improves chemotherapeutic responses by relieving immune suppression.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 1_Supplement ( 2013-01-01), p. B83-B83
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 1_Supplement ( 2013-01-01), p. B83-B83
    Abstract: Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination, and the induction of immune suppression. Far from being a static cell population, the presence of cancer stem cells appears to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact that immune responses have on the differentiation or expansion of tumor stem cells is not well understood. In this study, we demonstrate that targeting tumor-infiltrating macrophages and inflammatory monocytes by either inhibition of colony stimulating factor-1 receptor (CSF1R) or chemokine (C-C motif) receptor 2 (CCR2) decreases the number of tumor-initiating cells in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses. We also found that tumor-educated macrophages could directly enhance the tumor-initiating capacity of pancreatic tumor cells through the activation of signal transducer and activator of transcription 3 (STAT3). In turn, these STAT3-activated tumor-initiating cells facilitate macrophage-mediated suppression of CD8+ T lymphocytes. These data suggest that targeting tumor-infiltrating macrophages is an effective strategy for overcoming therapeutic resistance due to the presence of tumor-initiating cells. Citation Format: Jonathan B. Mitchem, Donal J. Brennan, Dominic E. Sanford, Brett L. Knolhoff, Yu Zhu, Belt Brian, Andrea Wang-Gillam, Peter Goedegebuure, David C. Linehan, David G. DeNardo. Targeting tumor-infiltrating macrophages decreases pancreatic tumor-initiating cells and improves chemotherapeutic responses by relieving immune suppression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B83.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TUMIMM2012-B83
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 6
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    Abstract 3303: Pre-clinical characterization of the novel FAP targeting ligand PNT6555 for imaging and therapy of cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3303-3303
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3303-3303
    Abstract: Background: Fibroblast Activation Protein-α (FAP) is a transmembrane glycoprotein highly expressed on activated fibroblasts. It is a constitutively active 170 kDa serine protease and a member of the dipeptide peptidase (DPP) family, sharing ~50% homology with DPPIV. FAP expression is only rarely expressed in normal adult tissues and is overexpressed in many epithelial cancers through upregulation on cancer-associated fibroblasts present in the stroma of various types of tumor. POINT BioPharma is developing PNT6555, which comprises a DOTA chelator linked to a FAP-targeting moiety, for imaging and therapeutic applications. Methods: PNT6555 and its radiometal chelates were evaluated for potency, selectivity, biodistribution and efficacy using biochemical and cellular assays as well as imaging, biodistribution and efficacy studies in tumor bearing mice. Results: PNT6555 and its gallium (natGa-PNT6555) and lutetium (natLu-PNT6555) chelates showed potent activity in FAP inhibition assays using human, mouse, and rat sources of FAP. PNT6555, natLu-PNT6555 and natGa-PNT6555 also showed significantly reduced potency when tested against PREP and DPPIV, two closely related homologous proteins. In vivo time-course biodistribution studies (by PET-imaging) with 68Ga-PNT6555 showed rapid clearance of 68Ga-PNT6555 from blood through the kidneys and urinary tract, with rising 68Ga-PNT6555 activity observed in the tumor through 60 minutes. At 60 minutes, the tumor was the only site of significant retained activity ( & gt;10 %ID/g). In vivo biodistribution studies (by SPECT imaging and direct organ assay) with 177Lu-PNT6555 showed rapid renal clearance into the bladder. After 24 hours, the tumor was the only tissue with significant activity retention. Direct organ assay showed little 177Lu-PNT6555 accumulation and retention in normal tissues with a high level of tumor retention observed out to 168h ( & gt;10 %ID/g). Therapeutic studies, using a single dose of 177Lu-PNT6555 or 225Ac-PNT6555, were completed in pre-clinical mouse models of cancer. In the HEK-mFAP model, significant dose responsive efficacy was observed in mice treated with either 177Lu-PNT6555 or 225Ac-PNT6555, with no apparent weight loss observed at all tested dose levels. Several mice experienced long-term survival & gt;100 days at multiple of the tested dose levels. Conclusions: PNT6555, and its radiometal chelates, are potent and specific inhibitors of FAP. 68Ga/177Lu-PNT6555 showed rapid and prolonged uptake into FAP expressing tumors with limited uptake or retention observed in normal tissues. 177Lu/225Ac-PNT6555 showed compelling efficacy in pre-clinical tumor models that expressed FAP. Clinical studies with imaging and therapeutic chelates of PNT6555 are warranted. Citation Format: Robin M. Hallett, Sarah E. Poplawski, Mark H. Dornan, Shin Hye Ahn, Shuang Pan, Wu Wengen, Liu Yuxin, David G. Sanford, Valerie S. Hergott, Quang-De Nguyen, Anthony P. Belanger, Jack H. Lai, William Bachovchin, Joe A. McCann. Pre-clinical characterization of the novel FAP targeting ligand PNT6555 for imaging and therapy of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3303.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-3303
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 7
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    Abstract 4730: Molecular analysis of the pediatric cancer fibrolamellar hepatocellular carcinoma
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4730-4730
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4730-4730
    Abstract: Genomic analysis of the pediatric cancer fibrolamellar hepatocellular carcinoma Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver tumor that usually occurs in adolescents and young adults. Originally considered a variant of hepatocellular carcinoma (HCC), FLHCC is characterized by hepatocytes with deeply eosinophilic, granular cytoplasm interspersed with fibrous bands, without signs of cirrhosis as in HCC. Since little is known of its molecular pathogenesis, we performed RNA-seq and whole genome sequencing of FLHCC paired with normal liver from the same patient. Our results demonstrated that the majority of the DNA is unremarkable with few recurrent mutations or structural variants such as amplifications or inversions The major finding is a heterogeneous deletion of ∼400 kB in chromosome 19 which produces a chimeric transcript and a fully functional protein, a fusion between the heat shock protein DNAJB1 and the catalytic subunit of protein kinase A (PRKACA). Our initial observation of this chimera in 15 out of 15 patients has now been expanded to 116 out of 116 patients. Differential expression analysis of RNA-seq revealed many changes in the gene expression in FLHCC as compared to its paired normal liver. These changes were highly consistent from patient to patient, suggesting a unifying pathogenesis. The RNA-seq from our FLHCC samples had little in common with HCC samples from the TCGA or published reports of other cancers. An analysis of protein expression correlated well with the RNA-seq results. Some observed changes can directly be linked to increased activity of PRKACA. Other changes involve pathways known to participate in the initiation and progression of other cancers, which, along with an increase of PRKACA activity, represent targets for therapeutic intervention. Several of these targets are now being explored in cellular models, genetic, and PDX mouse models, as well as clinical trials. Citation Format: Elana P. Simon, Joshua N. Honeyman, David G. Darcy, Brad R. Rosenberg, Iris I. Lim, Jennifer M. Murphy, Ben Farber, Gadi Lalazar, Catherine Freije, Michael P. La Quaglia, Sanford M. Simon. Molecular analysis of the pediatric cancer fibrolamellar hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4730. doi:10.1158/1538-7445.AM2015-4730
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4730
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 8
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    Abstract 1815: AVA6000, a novel Precision medicine, targeted to the tumor microenvironment via Fibroblast Activation Protein (FAP) mediated cleavage
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1815-1815
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1815-1815
    Abstract: AVA6000 is a therapeutic product based on proprietary pre|CISION™ technology which incorporates a substrate that is sensitive to cleavage by FAP. The pre|CISION™ substrate can be utilized in a drug conjugate linker or to generate chemotherapy prodrugs that are only activated in the tumor microenvironment. AVA6000 consists of a doxorubicin molecule covalently bonded to a dipeptide (pyridine-4-carbonyl)-D-Ala-L-Pro), which is designed to be susceptible to hydrolysis by Fibroblast Activation Protein α (FAP) but is resistant to hydrolysis by both closely related and wider mammalian peptidases. FAP, a post-prolyl endopeptidase, is overexpressed on the surface of activated fibroblastic cells which are abundant in the supporting stroma of over 90% of malignant epithelial cancers, as well as in bone and soft tissue sarcoma. While FAP is also present both in normal tissues and as a soluble enzyme in plasma, levels are significantly lower than those present in malignant epithelial cancers. Consequently, AVA6000 has the potential to deliver doxorubicin directly to the tumor microenvironment, while exposing the patient to a lesser degree of doxorubicin-associated toxicities. The primary mechanism of action of doxorubicin is thought to involve stabilisation of a topoisomerase-II-DNA cleavable complex through non-specific DNA-intercalation. The non-specific DNA-intercalation causes a number of downstream effects, which may ultimately result in apoptotic cell death. Although doxorubicin has been one of the most effective and widely used chemotherapeutic agents for the treatment of various solid malignancies for over 40 years, its clinical utility is limited by dose-limiting toxicities, including myelosuppression and cardiotoxicity. The unique FAP specificity of the N-(pyridine-4-carbonyl)-D-Ala-L-Pro leaving group conjugated to doxorubicin in AVA6000 is supported by the absence of cleavage of the fluorogenic analogue, 3114-AMC, in FAP gene-knockout mice (Fap-/-). In vitro cytotoxicity assessments involving human tumor cell lines showed that AVA6000 was between 80-fold to 4,000-fold less cytotoxic compared to doxorubicin. In several in vivo efficacy studies in tumours with high FAP levels, AVA6000 significantly decreased tumor volume and increased survival in a dose-dependent manner. In a PDX model of osteosarcoma, AVA6000 significantly decreased tumor volume while doxorubicin had no significant effect. The efficacy and tolerability profile of AVA6000 strongly support its clinical development, and a Phase I trial in patients with locally advanced or metastatic selected solid tumours in underway. Citation Format: Fiona McLaughlin, Sarah E. Poplawski, David G. Sanford, Andrew Saunders, Jack H. Lai, Matthew Vincent, William W. Bachovchin, Neil Bell. AVA6000, a novel Precision medicine, targeted to the tumor microenvironment via Fibroblast Activation Protein (FAP) mediated cleavage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1815.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1815
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    Methylated DNA Markers of Esophageal Squamous Cancer and Dysplasia: An International Study
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 12 ( 2020-12-01), p. 2642-2650
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 12 ( 2020-12-01), p. 2642-2650
    Abstract: Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices. Methods: MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons. Results: Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia (P & lt; 0.004). Conclusions: MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results. Impact: MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-20-0616
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 10
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    Abstract 2685: Identification of circulating protein biomarkers for colorectal cancer risk: A genetic instrument analysis
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2685-2685
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2685-2685
    Abstract: Colorectal cancer (CRC) is one of the most common cancers in United States and many countries in the world. There is an urgent need to better understand its etiology and identify novel biomarkers to facilitate the early detection of CRC. Previous studies either lacked sufficient power to identify novel biomarkers or provided inconsistent results. In the current study, we attempted to uncover novel protein biomarkers for CRC through an integrated analysis of genomics and proteomics data. We first constructed study instruments using genetic variants identified from a large-scale protein quantitative trait loci (pQTL) analysis for over 1,400 circulating proteins. We used beta coefficients and standard errors for these pQTL variants from two large consortia of European-ancestry populations, the Colorectal Transdisciplinary (CORECT) Study (11,895 cases and 14,659 controls) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) (22,974 cases and 14,392 controls) for association analyses for genetically predicted protein levels with CRC risk using an inverse-variance weighted method. The genetically predicted levels of six proteins were associated with CRC risk after accounting for multiple comparisons (Benjamini-Hochberg FDR & lt; 0.05). Among them, genetically predicted levels of VCAM-1, MIP-3b and LPH were inversely associated with CRC risk (VCAM-1: odds ratio [OR] per unit of increase = 0.65, Pmeta = 6.2 ×10-11; MIP-3b: OR = 0.68, Pmeta = 5.5×10-7; LPH: OR = 0.93, Pmeta = 8.0×10-5), while BMP-6, CRDL2 and laminin were positively associated (BMP-6: OR = 1.57, Pmeta = 3.0 ×10-9; CRDL2: OR = 1.36, Pmeta = 3.0 ×10-9; laminin: OR = 1.13, Pmeta = 6.7 ×10-5). Except for VCAM-1 (rs3184504, 12q24.12-SH2B3), other associations are not accounted for by any known CRC susceptibility variants. We observed a possible biological link connecting the genetic variants of LAMC1, LAMC1 expression, and laminin concentrations to CRC risk. Our study identifies potential novel biomarkers for CRC risk and provides novel insight into the disease etiology. Citation Format: Xiang Shu, Xiao-ou Shu, Jirong Long, Qiuyin Cai, Conghui Qu, Stephanie L. Schmit, Chenxu Qu, Sonja I. Berndt, Peter T. Campbell, Andrew T. Chan, Graham G. Giles, Andrea Gsur, Michael Hoffmeister, Mark A. Jenkins, Sanford D. Markowitz, Li Li, Gad Rennert, Kenneth Offit, David Conti, Annika Lindblom, Graham Casey, Stephen B. Gruber, Ulrike Peters, Wei Zheng. Identification of circulating protein biomarkers for colorectal cancer risk: A genetic instrument analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2685.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2685
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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