Publications by authors named "Marissa Mattar"

15 Publications

  • Page 1 of 1

Novel preclinical patient-derived lung cancer models reveal inhibition of HER3 and MTOR signaling as therapeutic strategies for NRG1 fusion-positive cancers.

J Thorac Oncol 2021 Apr 8. Epub 2021 Apr 8.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Introduction: NRG1 rearrangements produce chimeric ligands that subvert the ERBB pathway to drive tumorigenesis. A better understanding of the signaling networks that mediate transformation by NRG1 fusions is needed to inform effective therapeutic strategies. However, this has been hampered by a paucity of patient-derived disease models that faithfully recapitulate this molecularly defined cancer subset.

Methods: Patient-derived xenograft (PDX) and cell line models were established from NRG1-rearranged lung adenocarcinoma samples. Transcriptomic, proteomic and biochemical analyses were performed to identify activated pathways. Efficacy studies were conducted to evaluate HER3- and MTOR-directed therapies.

Results: We established a pair of PDX and cell line models of invasive mucinous lung adenocarcinoma (LUAD-0061AS3, SLC3A2-NRG1), representing the first reported paired in vitro/in vivo model of NRG1-driven tumors. Growth of LUAD-0061AS3 models was reduced by the anti-HER3 antibody GSK2849330. Transcriptomic profiling revealed activation of the MTOR pathway in lung tumor samples with NRG1 fusions. Phosphorylation of several MTOR effectors (S6 and 4EBP1) was higher in LUAD-0061AS3 cells compared to HBEC cells and the breast cancer cell line MDA-MB-175-VII (DOC4-NRG1 fusion). Accordingly, LUAD-0061AS3 cells were more sensitive to MTOR inhibitors than MDA-MB-175-VII cells and targeting the MTOR pathway with rapamycin blocked growth of LUAD-0061AS3 PDX tumors in vivo. In contrast, MDA-MB-175-VII breast cancer cells had higher MAPK pathway activation and were more sensitive to MEK inhibition.

Conclusions: We identify the MTOR pathway as a candidate vulnerability in NRG1 fusion-positive lung adenocarcinoma that may warrant further pre-clinical evaluation, with the eventual goal of finding additional therapeutic options for patients in whom ERBB-directed therapy fails. Moreover, our results uncover heterogeneity in downstream oncogenic signaling among NRG1-rearranged cancers, possibly histology-dependent, the therapeutic significance of which requires additional investigation.
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http://dx.doi.org/10.1016/j.jtho.2021.03.013DOI Listing
April 2021

The Anti-HER3 mAb Seribantumab Effectively Inhibits Growth of Patient-Derived and Isogenic Cell Line and Xenograft Models with Oncogenic Fusions.

Clin Cancer Res 2021 Apr 6. Epub 2021 Apr 6.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Oncogenic fusions involving the () gene are found in approximately 0.2% of cancers of diverse histologies. The resulting chimeric NRG1 proteins bind predominantly to HER3, leading to HER3-HER2 dimerization and activation of downstream growth and survival pathways. HER3 is, therefore, a rational target for therapy in NRG1 fusion-driven cancers.

Experimental Design: We developed novel patient-derived and isogenic models of NRG1-rearranged cancers and examined the effect of the anti-HER3 antibody, seribantumab, on growth and activation of signaling networks and RESULTS: Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, fusion) and lung (LUAD-0061AS3, fusion) cancer cells harboring fusions or amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of proapoptotic proteins and reduced expression of the cell-cycle regulator, cyclin D1, were observed in seribantumab-treated cells. Treatment of MDA-MB-175-VII, LUAD-0061AS3, and HBECp53-CD74-NRG1 cells with seribantumab reduced phosphorylation of EGFR, HER2, HER3, HER4, and known downstream signaling molecules, such as AKT and ERK1/2. Significantly, administration of seribantumab to mice bearing LUAD-0061AS3 patient-derived xenograft (PDX) and OV-10-0050 (ovarian cancer with fusion) PDX tumors induced regression of tumors by 50%-100%. Afatinib was much less effective at blocking tumor growth.

Conclusions: Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of fusion-dependent tumorigenesis and in breast, lung, and ovarian patient-derived cancer models.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3605DOI Listing
April 2021

NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors.

Commun Biol 2020 Dec 16;3(1):776. Epub 2020 Dec 16.

Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.

Tyrosine kinase domains dynamically fluctuate between two main structural forms that are referred to as type I (DFG-in) or type II (DFG-out) conformations. Comprehensive data comparing type I and type II inhibitors are currently lacking for NTRK fusion-driven cancers. Here we used a type II NTRK inhibitor, altiratinib, as a model compound to investigate its inhibitory potential for larotrectinib (type I inhibitor)-resistant mutations in NTRK. Our study shows that a subset of larotrectinib-resistant NTRK1 mutations (V573M, F589L and G667C) retains sensitivity to altiratinib, while the NTRK1 and xDFG motif NTRK1 mutations are highly sensitive to type II inhibitors, including altiratinib, cabozantinib and foretinib. Moreover, molecular modeling suggests that the introduction of a sulfur moiety in the binding pocket, via methionine or cysteine substitutions, specifically renders the mutant kinase hypersensitive to type II inhibitors. Future precision treatment strategies may benefit from selective targeting of these kinase mutants based on our findings.
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http://dx.doi.org/10.1038/s42003-020-01508-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745027PMC
December 2020

RET inhibition in novel patient-derived models of RET-fusion positive lung adenocarcinoma reveals a role for MYC upregulation.

Dis Model Mech 2020 Dec 14. Epub 2020 Dec 14.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring rearrangements. Here we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-derived cell line, and several isogenic cell lines with RET fusions. Using these models, we re-examined the efficacy and mechanism of action of cabozantinib and found that this RET inhibitor was effective at blocking growth of cell lines, activating caspase 3/7 and inhibiting activation of ERK and AKT. Cabozantinib treatment of mice bearing RET-fusion-positive cell line xenografts and two PDXs significantly reduced tumor proliferation without adverse toxicity. Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105. Transcriptomic analysis of lung tumors and cell lines with RET alterations showed activation of a MYC signature and this was suppressed by treatment of cell lines with cabozantinib. MYC protein levels were rapidly depleted following cabozantinib treatment. Taken together, our results demonstrate that cabozantinib is an effective agent in preclinical models harboring rearrangements with three different 5' fusion partners (, and ). Notably, we identify MYC as a protein that is upregulated by RET expression and down-regulated by cabozantinib treatment, opening up potentially new therapeutic avenues for combinatorial targeting RET-fusion driven lung cancers. The novel RET fusion-dependent preclinical models described herein represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies.
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http://dx.doi.org/10.1242/dmm.047779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888717PMC
December 2020

Therapeutic Potential of NTRK3 Inhibition in Desmoplastic Small Round Cell Tumor.

Clin Cancer Res 2021 Feb 23;27(4):1184-1194. Epub 2020 Nov 23.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Desmoplastic small round cell tumor (DSRCT) is a highly lethal intra-abdominal sarcoma of adolescents and young adults. DSRCT harbors a t(11;22)(p13:q12) that generates the EWSR1-WT1 chimeric transcription factor, the key oncogenic driver of DSRCT. EWSR1-WT1 rewires global gene expression networks and activates aberrant expression of targets that together mediate oncogenesis. EWSR1-WT1 also activates a neural gene expression program.

Experimental Design: Among these neural markers, we found prominent expression of neurotrophic tyrosine kinase receptor 3 (NTRK3), a druggable receptor tyrosine kinase. We investigated the regulation of NTRK3 by EWSR1-WT1 and its potential as a therapeutic target and , the latter using novel patient-derived models of DSRCT.

Results: We found that EWSR1-WT1 binds upstream of and activates its transcription. NTRK3 mRNA is highly expressed in DSRCT compared with other major chimeric transcription factor-driven sarcomas and most DSRCTs are strongly immunoreactive for NTRK3 protein. Remarkably, expression of kinase domain mRNA in DSRCT is also higher than in cancers with fusions. Abrogation of NTRK3 expression by RNAi silencing reduces growth of DSRCT cells and pharmacologic targeting of NTRK3 with entrectinib is effective in both and models of DSRCT.

Conclusions: Our results indicate that EWSR1-WT1 directly activates NTRK3 expression in DSRCT cells, which are dependent on its expression and activity for growth. Pharmacologic inhibition of NTRK3 by entrectinib significantly reduces growth of DSRCT cells both and , providing a rationale for clinical evaluation of NTRK3 as a therapeutic target in DSRCT.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2585DOI Listing
February 2021

Impact of tumor heterogeneity and microenvironment in identifying neoantigens in a patient with ovarian cancer.

Cancer Immunol Immunother 2021 May 29;70(5):1189-1202. Epub 2020 Oct 29.

Molecular Pharmacology Program, SKI, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Identification of neoepitopes as tumor-specific targets remains challenging, especially for cancers with low mutational burden, such as ovarian cancer. To identify mutated human leukocyte antigen (HLA) ligands as potential targets for immunotherapy in ovarian cancer, we combined mass spectrometry analysis of the major histocompatibility complex (MHC) class I peptidomes of ovarian cancer cells with parallel sequencing of whole exome and RNA in a patient with high-grade serous ovarian cancer. Four of six predicted mutated epitopes capable of binding to HLA-A*02:01 induced peptide-specific T cell responses in blood from healthy donors. In contrast, all six peptides failed to induce autologous peptide-specific response by T cells in peripheral blood or tumor-infiltrating lymphocytes from ascites of the patient. Surprisingly, T cell responses against a low-affinity p53-mutant Y220C epitope were consistently detected in the patient with either unprimed or in vitro peptide-stimulated T cells even though the patient's primary tumor did not bear this mutation. Our results demonstrated that tumor heterogeneity and distinct immune microenvironments within a patient should be taken into consideration for identification of immunogenic neoantigens. T cell responses to a driver gene-derived p53 Y220C mutation in ovarian cancer warrant further study.
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http://dx.doi.org/10.1007/s00262-020-02764-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053669PMC
May 2021

HER2-Mediated Internalization of Cytotoxic Agents in Amplified or Mutant Lung Cancers.

Cancer Discov 2020 May 25;10(5):674-687. Epub 2020 Mar 25.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Amplification of and oncogenic mutations in , the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with -amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy. SIGNIFICANCE: T-DM1 is clinically effective in lung cancers with amplification of or mutations in . This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196485PMC
May 2020

MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by Fusions.

Clin Cancer Res 2020 06 2;26(12):2932-2945. Epub 2020 Mar 2.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes.

Experimental Design: ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines.

Results: Eight of the 75 patients with a fusion had a concurrent MAPK pathway alteration and this correlated with shorter overall survival. In addition, the induction of ROS1 fusions stimulated activation of MEK/ERK signaling with minimal effects on AKT signaling, suggesting the importance of the MAPK pathway in driving ROS1 fusion-positive cancers. Of 8 patients, 2 patients harbored novel in-frame deletions in MEK1 (MEK1delE41_L54) and MEKK1 (MEKK1delH907_C916) that were acquired after ROS1 TKIs, and 2 patients harbored loss-of-function mutations. Expression of MEK1del or MEKK1del, and knockdown of in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del.

Conclusions: We demonstrate that downstream activation of the MAPK pathway can mediate of innate acquired resistance to ROS1 TKIs and that patients harboring ROS1 fusion and concurrent downstream MAPK pathway alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034819PMC
June 2020

Regenerative lineages and immune-mediated pruning in lung cancer metastasis.

Nat Med 2020 02 10;26(2):259-269. Epub 2020 Feb 10.

Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.
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http://dx.doi.org/10.1038/s41591-019-0750-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021003PMC
February 2020

Complete Pathological Response to Crizotinib in a Patient with ALK-rearranged Lung Adenocarcinoma.

Clin Lung Cancer 2020 01 13;21(1):e25-e29. Epub 2019 Oct 13.

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

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http://dx.doi.org/10.1016/j.cllc.2019.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996866PMC
January 2020

Resistance to TRK inhibition mediated by convergent MAPK pathway activation.

Nat Med 2019 09 12;25(9):1422-1427. Epub 2019 Aug 12.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.
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http://dx.doi.org/10.1038/s41591-019-0542-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736691PMC
September 2019

and Amplifications Determine Response to HER2 Inhibition in -Amplified Esophagogastric Cancer.

Cancer Discov 2019 02 21;9(2):199-209. Epub 2018 Nov 21.

Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.

The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of and . Heterogeneous Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking amplification or with acquisition of amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in and coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in -amplified EG cancer. SIGNIFICANCE: Analysis of patients with -amplified, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with / coamplification and amplification, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones...
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http://dx.doi.org/10.1158/2159-8290.CD-18-0598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368868PMC
February 2019

Activation of KRAS Mediates Resistance to Targeted Therapy in MET Exon 14-mutant Non-small Cell Lung Cancer.

Clin Cancer Res 2019 02 23;25(4):1248-1260. Epub 2018 Oct 23.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: exon 14 splice site alterations that cause exon skipping at the mRNA level (ex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear.

Experimental Design: We examined clinical and genomic data from 113 patients with lung cancer with ex14. MET TKI resistance due to mutation was functionally evaluated using and models.

Results: Five of 113 patients (4.4%) with ex14 had concurrent G12 mutations, a rate of cooccurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the mutation was acquired post-crizotinib, while the remaining 4 ex14 patients harbored the mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with ex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models.

Conclusions: mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in ex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377821PMC
February 2019

Establishing and Maintaining an Extensive Library of Patient-Derived Xenograft Models.

Front Oncol 2018 19;8:19. Epub 2018 Feb 19.

Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States.

Patient-derived xenograft (PDX) models have recently emerged as a highly desirable platform in oncology and are expected to substantially broaden the way studies are designed and executed and to reshape drug discovery programs. However, acquisition of patient-derived samples, and propagation, annotation and distribution of PDXs are complex processes that require a high degree of coordination among clinic, surgery and laboratory personnel, and are fraught with challenges that are administrative, procedural and technical. Here, we examine in detail the major aspects of this complex process and relate our experience in establishing a PDX Core Laboratory within a large academic institution.
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http://dx.doi.org/10.3389/fonc.2018.00019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825907PMC
February 2018

Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy.

Oncoimmunology 2016 Jul 25;5(7):e1151595. Epub 2016 Apr 25.

Swim Across America/Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center , New York, NY, USA.

Unlabelled: Colony stimulating factor-1 (CSF-1) is produced by a variety of cancers and recruits myeloid cells that suppress antitumor immunity, including myeloid-derived suppressor cells (MDSCs.) Here, we show that both CSF-1 and its receptor (CSF-1R) are frequently expressed in tumors from cancer patients, and that this expression correlates with tumor-infiltration of MDSCs. Furthermore, we demonstrate that these tumor-infiltrating MDSCs are highly immunosuppressive but can be reprogrammed toward an antitumor phenotype in vitro upon CSF-1/CSF-1R signaling blockade. Supporting these findings, we show that inhibition of CSF-1/CSF-1R signaling using an anti-CSF-1R antibody can regulate both the number and the function of MDSCs in murine tumors in vivo. We further find that treatment with anti-CSF-1R antibody induces antitumor T-cell responses and tumor regression in multiple tumor models when combined with CTLA-4 blockade therapy. However, this occurs only when administered after or concurrent with CTLA-4 blockade, indicating that timing of each therapeutic intervention is critical for optimal antitumor responses. Importantly, MDSCs present within murine tumors after CTLA-4 blockade showed increased expression of CSF-1R and were capable of suppressing T cell proliferation, and CSF-1/CSF-1R expression in the human tumors was not reduced after treatment with CTLA-4 blockade immunotherapy. Taken together, our findings suggest that CSF-1R-expressing MDSCs can be targeted to modulate the tumor microenvironment and that timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to checkpoint based immunotherapy.

Significance: Infiltration by immunosuppressive myeloid cells contributes to tumor immune escape and can render patients resistant or less responsive to therapeutic intervention with checkpoint blocking antibodies. Our data demonstrate that blocking CSF-1/CSF-1R signaling using a monoclonal antibody directed to CSF-1R can regulate both the number and function of tumor-infiltrating immunosuppressive myeloid cells. In addition, our findings suggest that reprogramming myeloid responses may be a key in effectively enhancing cancer immunotherapy, offering several new potential combination therapies for future clinical testing. More importantly for clinical trial design, the timing of these interventions is critical to achieving improved tumor protection.
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http://dx.doi.org/10.1080/2162402X.2016.1151595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006914PMC
July 2016