Publications by authors named "Carl M Gay"

29 Publications

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Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer.

Cancer Metab 2021 Sep 23;9(1):33. Epub 2021 Sep 23.

Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Introduction: The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches.

Methods: We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3.

Results: MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression.

Conclusions: Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.
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http://dx.doi.org/10.1186/s40170-021-00270-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461854PMC
September 2021

Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer.

J Immunother Cancer 2021 Aug;9(8)

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Non-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.

Methods: Three cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.

Results: High PD-L1 expression (PD-L1 ≥50%) rate was 19%-20% in classic , exon 20 and -mutant tumors, and 34%-55% in tumors with , V600E, , , or alterations. Compared with mutant tumors, non-V600E group had higher TMB (9.6 vs 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p<0.001). In the two clinical cohorts treated with ICB, molecular groups with , , , , , or alterations had short progression-free survival (PFS; 1.8-3.7 months), while V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs 24%; PFS 7.4 vs 2.8 months, HR 0.36, p=0.026). G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p<0.001) were associated with longer PFS.

Conclusions: High TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile and mutations and , , , and fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.
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http://dx.doi.org/10.1136/jitc-2021-002891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356172PMC
August 2021

Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2-Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology.

J Thorac Oncol 2021 Jul 16. Epub 2021 Jul 16.

Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Introduction: Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which enters host cells through the cell surface proteins ACE2 and TMPRSS2.

Methods: Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2.

Results: We find that ACE2 expression is restricted to a select population of epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium induces metabolic and transcriptional changes consistent with epithelial-to-mesenchymal transition (EMT), including up-regulation of ZEB1 and AXL, resulting in an increased EMT score. In addition, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT through the transforming growth factor-β, ZEB1 overexpression, and onset of EGFR tyrosine kinase inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL inhibition and ZEB1 reduction, as with bemcentinib, offer a potential strategy to reverse this effect.

Conclusions: These observations highlight the use of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses and offer important insights into the potential mechanisms underlying the morbidity and mortality of coronavirus disease 2019 in healthy patients and patients with cancer alike.
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http://dx.doi.org/10.1016/j.jtho.2021.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282443PMC
July 2021

Veliparib in Combination with Carboplatin and Etoposide in Patients with Treatment-Naïve Extensive-Stage Small Cell Lung Cancer: A Phase 2 Randomized Study.

Clin Cancer Res 2021 Jul 4;27(14):3884-3895. Epub 2021 May 4.

Juravinski Cancer Center, McMaster University, Hamilton, Ontario, Canada.

Purpose: This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC).

Patients And Methods: Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4-6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control.

Results: Overall ( = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50-0.88; = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36-0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09-1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic.

Conclusions: Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4259DOI Listing
July 2021

Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer.

Nat Cancer 2020 Apr 17;1:423-436. Epub 2020 Feb 17.

Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The natural history of small cell lung cancer (SCLC) includes rapid evolution from chemosensitivity to chemoresistance, although mechanisms underlying this evolution remain obscure due to scarcity of post-relapse tissue samples. We generated circulating tumor cell (CTC)-derived xenografts (CDXs) from SCLC patients to study intratumoral heterogeneity (ITH) via single-cell RNAseq of chemo-sensitive and -resistant CDXs and patient CTCs. We found globally increased ITH including heterogeneous expression of therapeutic targets and potential resistance pathways, such as EMT, between cellular subpopulations following treatment-resistance. Similarly, serial profiling of patient CTCs directly from blood confirmed increased ITH post-relapse. These data suggest that treatment-resistance in SCLC is characterized by coexisting subpopulations of cells with heterogeneous gene expression leading to multiple, concurrent resistance mechanisms. These findings emphasize the need for clinical efforts to focus on rational combination therapies for treatment-naïve SCLC tumors to maximize initial responses and counteract the emergence of ITH and diverse resistance mechanisms.
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http://dx.doi.org/10.1038/s43018-019-0020-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842382PMC
April 2020

Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities.

Cancer Cell 2021 03 21;39(3):346-360.e7. Epub 2021 Jan 21.

Department of Thoracic/Head & Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data and non-negative matrix factorization, we identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts induces intratumoral shifts toward SCLC-I, supporting subtype switching as a mechanism of acquired platinum resistance. We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients.
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http://dx.doi.org/10.1016/j.ccell.2020.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143037PMC
March 2021

Narrative review of the emerging role of molecular biomarkers in guiding the definitive management of unresectable non-small cell lung cancer.

Transl Lung Cancer Res 2020 Oct;9(5):2051-2058

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.

The addition of PD-L1 targeting consolidation therapy to previously standard of care concurrent chemoradiation for locally advanced, unresectable non-small cell lung cancer resulted in dramatic improvements in clinical outcomes. However, in contrast to patients with metastatic disease, the application of immunotherapies is not currently guided by molecular characteristics of patient tumors. Furthermore, despite increasing awareness of predictive and/or prognostic genomic alterations in patients with locally advanced disease, the utility of targeted therapies, such as those aimed at alterations in or , remains unclear in this subset of patients. As a result, patients with unresectable, locally advanced non-small cell lung cancer are treated uniformly according to histology, regardless of other molecular features despite the potential for treatment-associated risks without a clear benefit. Here, we first discuss the advantages of utilizing molecular biomarkers to guide treatment of non-small cell lung cancer based on treatment outcomes in the metastatic setting. Next, we review preclinical and retrospective clinical data that supports potential further personalization of these treatment strategies in earlier stages of disease. Finally, we discuss some of the ongoing clinical trials attempting to address these hypotheses prospectively.
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http://dx.doi.org/10.21037/tlcr-20-330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653123PMC
October 2020

Toxicity and Survival After Intensity-Modulated Proton Therapy Versus Passive Scattering Proton Therapy for NSCLC.

J Thorac Oncol 2021 02 22;16(2):269-277. Epub 2020 Oct 22.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Objective: Although intensity-modulated radiation therapy (IMPT) is dosimetrically superior to passive scattering proton therapy (PSPT) for locally advanced NSCLC (LA-NSCLC), direct comparisons of clinical outcomes are lacking. Here, we compare toxicity profiles and clinical outcomes after IMPT versus PSPT for LA-NSCLC.

Methods: This is a nonrandomized, comparative study of two independent cohorts with LA-NSCLC (stage II-IIIB, stage IV with solitary brain metastasis) treated with concurrent chemotherapy and proton beam therapy. Toxicity (Common Terminology Criteria for Adverse Events version 4.0) and outcomes were prospectively collected as part of a clinical trial (ClinicalTrials.gov identifier NCT00915005) or prospective registry (ClinicalTrials.gov identifier NCT00991094).

Results: Of 139 patients, 86 (62%) received PSPT and 53 (38%) IMPT; median follow-up times were 23.9 and 29.0 months, respectively. IMPT delivered lower mean radiation doses to the lungs (PSPT 16.0 Gy versus IMPT 13.0 Gy, p < 0.001), heart (10.7 Gy versus 6.6 Gy, p = 0.004), and esophagus (27.4 Gy versus 21.8 Gy, p = 0.005). Consequently, the IMPT cohort had lower rates of grade 3 or higher pulmonary (17% versus 2%, p = 0.005) and cardiac (11% versus 0%, p = 0.01) toxicities. Six patients (7%) with PSPT and zero patients (0%) with IMPT experienced grade 4 or 5 toxicity. Lower rates of pulmonary (28% versus 3%, p = 0.006) and cardiac (14% versus 0%, p = 0.05) toxicities were observed in the IMPT cohort even after propensity score matching for baseline imbalances. There was also a trend toward longer median overall survival in the IMPT group (23.9 mo versus 36.2 mo, p = 0.09). No difference was found in the 3-year rates of local (25% versus 20%, p = 0.44), local-regional (29% versus 36%, p = 0.56) and distant (52% versus 51%, p = 0.71) recurrences.

Conclusions: IMPT is associated with lower radiation doses to the lung, heart, and esophagus, and lower rates of grade 3 or higher cardiopulmonary toxicity; additional clinical studies will be needed to assess the potential differences in survival between the two techniques.
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http://dx.doi.org/10.1016/j.jtho.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855203PMC
February 2021

AXL Inhibition Induces DNA Damage and Replication Stress in Non-Small Cell Lung Cancer Cells and Promotes Sensitivity to ATR Inhibitors.

Mol Cancer Res 2021 03 10;19(3):485-497. Epub 2020 Nov 10.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

AXL, a TAM (TYRO3, AXL, and MERTK) family receptor tyrosine kinase, is increasingly being recognized as a key determinant of resistance to targeted therapies, as well as chemotherapy and radiation in non-small cell lung cancer (NSCLC) and other cancers. We further show here that high levels of and epithelial-to-mesenchymal transition were frequently expressed in subsets of both treatment-naïve and treatment-relapsed NSCLC. Previously, we and others have demonstrated a role for AXL in mediating DNA damage response (DDR), as well as resistance to inhibition of WEE1, a replication stress response kinase. Here, we show that BGB324 (bemcentinib), a selective small-molecule AXL inhibitor, caused DNA damage and induced replication stress, indicated by ATR/CHK1 phosphorylation, more significantly in -deficient NSCLC cell lines. Similar effects were also observed in large-cell neuroendocrine carcinoma (LCNEC) cell lines. High AXL protein levels were also associated with resistance to ATR inhibition. Combined inhibition of AXL and ATR significantly decreased cell proliferation of NSCLC and LCNEC cell lines. Mechanistically, combined inhibition of AXL and ATR significantly increased RPA32 hyperphosphorylation and DNA double-strand breaks and induced markers of mitotic catastrophe. Notably, NSCLC cell lines with low levels of SLFN11, a known predictive biomarker for platinum and PARP inhibitor sensitivity, were more sensitive to AXL/ATR cotargeting. These findings demonstrate a novel and unexpected role for AXL in replication stress tolerance, with potential therapeutic implications. IMPLICATIONS: These findings demonstrate that the combination of AXL and ATR inhibitors could be a promising therapeutic combination for NSCLC, LCNEC, and other cancers.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925356PMC
March 2021

A Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma.

Oncologist 2020 10 19;25(10):e1457-e1463. Epub 2020 Jul 19.

Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Lessons Learned: Treatment with the Aurora kinase A inhibitor yields often durable disease control, but limited tumor regression, in heavily pretreated patients with unresectable malignant pleural or peritoneal mesothelioma. In a limited sample size, MYC copy-number gain or gene amplification, a candidate predictive biomarker for alisertib, did not correlate with improved response numbers or patient outcomes.

Background: Malignant mesothelioma is an aggressive disease for which few effective therapies are available. The Aurora family kinases are critical for mitotic fidelity and highly expressed in mesothelioma, wherein their inhibition leads to growth arrest in vitro. We evaluated the efficacy of alisertib, an Aurora A kinase inhibitor, in relapsed malignant mesothelioma.

Methods: Twenty-six patients with previously treated, unresectable pleural or peritoneal mesothelioma were enrolled on a single-arm, single-institution phase II trial of alisertib at a dosage of 50 mg twice daily for 7 of every 21 days. The primary endpoint was 4-month disease control rate. Secondary endpoints included overall response rate, progression free survival, overall survival, safety/toxicity, and correlation of endpoints with MYC copy number.

Results: Of the 25 evaluable patients treated on study, 8 (32%) experienced 4-month disease control, surpassing the futility endpoint. There were no confirmed partial or complete responses. Median progression-free and overall survival were 2.8 months and 6.3 months, respectively. No associations between MYC copy number and outcomes were observed.

Conclusion: Alisertib has modest activity in this unselected malignant mesothelioma population. Several patients achieved durable disease control. Although the study did meet its prespecified futility endpoint, the sponsor elected to close the trial at the interim analysis.
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http://dx.doi.org/10.1634/theoncologist.2020-0610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543335PMC
October 2020

Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology.

bioRxiv 2021 Jan 28. Epub 2021 Jan 28.

Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

COVID-19 is an infectious disease caused by SARS-CoV-2, which enters host cells via the cell surface proteins ACE2 and TMPRSS2. Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of and . We find that expression is restricted to a select population of highly epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium, induces metabolic and transcriptional changes consistent with epithelial to mesenchymal transition (EMT), including upregulation of and , resulting in an increased EMT score. Additionally, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT via TGFbeta, ZEB1 overexpression and onset of EGFR TKI inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL-inhibition and ZEB1-reduction, as with bemcentinib, offers a potential strategy to reverse this effect. These observations highlight the utility of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses, and offer important insights into the potential mechanisms underlying the morbidity and mortality of COVID-19 in healthy patients and cancer patients alike.
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http://dx.doi.org/10.1101/2020.05.28.122291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302206PMC
January 2021

Effects of Surgery on Survival of Early-Stage Patients With SCLC: Propensity Score Analysis and Nomogram Construction in SEER Database.

Front Oncol 2020 24;10:626. Epub 2020 Apr 24.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Medical Oncology, Peking University Cancer Hospital & Institute, Beijing, China.

We aimed to assess the survival benefit of surgery for patients with stage IA-IIB small cell lung cancer (SCLC) and construct a nomogram for predicting overall survival (OS). Patients who had been diagnosed with stage IA-IIB SCLC between 2004 and 2014 and who had received active treatment were selected from the Surveillance, Epidemiology, and End Results database. The primary endpoint was OS. Cox proportional hazards models and propensity score (PS) analyses were used to compare the associations between surgery and OS. The probability of 1- and 3-year OS was predicted using a nomogram. We reviewed 2,246 patients. The median OS of the surgery and non-surgery groups was 35 months and 19 months, respectively. Multivariable Cox proportional hazards models showed a survival benefit in the surgery group (hazards ratio [HR], 0.642; 95% confidence interval [CI], 0.557-0.740; < 0.001). To balance the between-group measurable confounders, the impact of surgery on OS was assessed using PS matching. After PS matching, OS analysis still favored surgical resection. The PS-stratification, PS-weighting, and PS-adjustment models showed similar results to demonstrate a statistically significant benefit for surgery. Further, the nomogram was well calibrated and had good discriminative ability (Harrell's -index = 0.645). Our analysis suggests that surgery is a viable option for patients with early-stage SCLC. Our nomogram is a viable tool for quantifying treatment trade-off assumptions and may assist clinicians in decision-making. Future work is needed to validate our results and improve our tools.
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http://dx.doi.org/10.3389/fonc.2020.00626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193096PMC
April 2020

Programmed Death-Ligand 1 Heterogeneity and Its Impact on Benefit From Immune Checkpoint Inhibitors in NSCLC.

J Thorac Oncol 2020 09 8;15(9):1449-1459. Epub 2020 May 8.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Introduction: Programmed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC.

Methods: PD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed.

Results: PD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (<1%, 1%-49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival.

Conclusions: PD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2020.04.026DOI Listing
September 2020

STING Pathway Expression Identifies NSCLC With an Immune-Responsive Phenotype.

J Thorac Oncol 2020 05 15;15(5):777-791. Epub 2020 Feb 15.

Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Introduction: Although the combination of anti-programmed cell death-1 or anti-programmed cell death ligand-1 (PD-L1) with platinum chemotherapy is a standard of care for NSCLC, clinical responses vary. Even though predictive biomarkers (which include PD-L1 expression, tumor mutational burden, and inflamed immune microenvironment) are validated for immunotherapy, their relevance to chemoimmunotherapy combinations is less clear. We have recently reported that activation of the stimulator of interferon genes (STING) innate immune pathway enhances immunotherapy response in SCLC. Here, we hypothesize that STING pathway activation may predict and underlie predictive correlates of antitumor immunity in NSCLC.

Methods: We analyzed transcriptomic and proteomic profiles in two NSCLC cohorts from our institution (treatment-naive patients in the Profiling of Resistance Patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax study and relapsed patients in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination study) and The Cancer Genome Atlas (N = 1320). Tumors were stratified by STING activation on the basis of protein or mRNA expression of cyclic GMP-AMP synthase, phospho-STING, and STING-mediated chemokines (chemokine ligand 5 [CCL5] and C-X-C motif chemokine 10 [CXCL10]). STING activation in patient tumors and in platinum-treated preclinical NSCLC models was correlated with biomarkers of immunotherapy response.

Results: STING activation is associated with higher levels of intrinsic DNA damage, targetable immune checkpoints, and chemokines in treatment-naive and relapsed lung adenocarcinoma. We observed that tumors with lower STING and immune gene expression show higher frequency of serine-threonine kinase 11 (STK11) mutations; however, we identified a subset of these tumors that are TP53 comutated and display high immune- and STING-related gene expression. Treatment with cisplatin increases STING pathway activation and PD-L1 expression in multiple NSCLC preclinical models, including adeno- and squamous cell carcinoma.

Conclusions: STING pathway activation in NSCLC predicts features of immunotherapy response and is enhanced by cisplatin treatment. This suggests a possible predictive biomarker and mechanism for improved response to chemoimmunotherapy combinations.
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http://dx.doi.org/10.1016/j.jtho.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202130PMC
May 2020

This Is Our Cells Under Pressure: Decreased DNA Damage Repair in Response to Targeted Therapies Facilitates the Emergence of Drug-Resistant Clones.

Cancer Cell 2020 01;37(1):5-7

Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

In a recent issue of Science, Russo et al. observe that colorectal cancer cells, when exposed to the pressure of EGFR- and BRAF-targeted therapies, transiently alter their transcriptional profiles to foster mutagenesis, thereby enhancing the stochastic development of acquired resistance mutations.
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http://dx.doi.org/10.1016/j.ccell.2019.12.005DOI Listing
January 2020

Combination Treatment of the Oral CHK1 Inhibitor, SRA737, and Low-Dose Gemcitabine Enhances the Effect of Programmed Death Ligand 1 Blockade by Modulating the Immune Microenvironment in SCLC.

J Thorac Oncol 2019 12 27;14(12):2152-2163. Epub 2019 Aug 27.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Introduction: Despite the enthusiasm surrounding cancer immunotherapy, most SCLC patients show very modest response to immune checkpoint inhibitor monotherapy treatment. Therefore, there is growing interest in combining immune checkpoint blockade with chemotherapy and other treatments to enhance immune checkpoint blockade efficacy. Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the U.S. Food and Drug Administration for frontline treatment for SCLC.

Methods And Results: Here, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti-programmed death ligand 1 (PD-L1) leads to an antitumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737 + anti-PD-L1/anti-PD-1 significantly increased antitumorigenic CD8+ cytotoxic T cells, dendritic cells, and M1 macrophage populations in an SCLC model. This regimen also led to a significant decrease in immunosuppressive M2 macrophage and myeloid-derived suppressor cell populations, as well as an increase in the expression of the type I interferon beta 1 gene, IFNβ, and chemokines, CCL5 and CXCL10.

Conclusions: Given that anti-PD-L1/anti-PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of the PD-L1/PD-1 pathway.
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http://dx.doi.org/10.1016/j.jtho.2019.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141083PMC
December 2019

PARP Inhibition Combined with Immune Checkpoint Blockade in SCLC: Oasis in an Immune Desert or Mirage?

J Thorac Oncol 2019 08;14(8):1323-1326

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2019.05.004DOI Listing
August 2019

GIPC proteins negatively modulate Plexind1 signaling during vascular development.

Elife 2019 05 3;8. Epub 2019 May 3.

Department of Cell Biology, Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, United States.

Semaphorins (SEMAs) and their Plexin (PLXN) receptors are central regulators of metazoan cellular communication. SEMA-PLXND1 signaling plays important roles in cardiovascular, nervous, and immune system development, and cancer biology. However, little is known about the molecular mechanisms that modulate SEMA-PLXND1 signaling. As PLXND1 associates with GIPC family endocytic adaptors, we evaluated the requirement for the molecular determinants of their association and PLXND1's vascular role. Zebrafish that endogenously express a Plxnd1 receptor with a predicted impairment in GIPC binding exhibit low penetrance angiogenesis deficits and antiangiogenic drug hypersensitivity. Moreover, mutant fish show angiogenic impairments that are ameliorated by reducing Plxnd1 signaling. Finally, depletion potentiates SEMA-PLXND1 signaling in cultured endothelial cells. These findings expand the vascular roles of GIPCs beyond those of the Vascular Endothelial Growth Factor (VEGF)-dependent, proangiogenic GIPC1-Neuropilin 1 complex, recasting GIPCs as negative modulators of antiangiogenic PLXND1 signaling and suggest that PLXND1 trafficking shapes vascular development.
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http://dx.doi.org/10.7554/eLife.30454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499541PMC
May 2019

PARP Inhibitors: Extending Benefit Beyond -Mutant Cancers.

Clin Cancer Res 2019 07 13;25(13):3759-3771. Epub 2019 Feb 13.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. Although PARP inhibitors as a class display many similarities, critical differences in structure can translate into differences in tolerability and antitumor activity that have important implications for the clinic. Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small-cell lung cancer. In this article, we highlight the key similarities and differences between individual PARP inhibitors and their implications for the clinic. We discuss data that currently support clinical strategies for extending the benefit of PARP inhibitors beyond -mutant cancers, toward broader populations of patients through the use of novel biomarkers of homologous recombination repair deficiency (HRD), as well as predictive biomarkers rooted in mechanisms of sensitivity outside of HRD. We also explore the potential application of PARP inhibitors in earlier treatment settings, including neoadjuvant, adjuvant, and even chemoprevention approaches. Finally, we focus on promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non-DDR-targeted agents that induce "chemical BRCAness."
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0968DOI Listing
July 2019

Beyond chemotherapy: Emerging biomarkers and therapies as small cell lung cancer enters the immune checkpoint era.

Cancer 2019 02 8;125(4):496-498. Epub 2019 Jan 8.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1002/cncr.31863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353664PMC
February 2019

Integrative Molecular Characterization of Malignant Pleural Mesothelioma.

Cancer Discov 2018 12 15;8(12):1548-1565. Epub 2018 Oct 15.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with and mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with and mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene in epithelioid MPM...
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http://dx.doi.org/10.1158/2159-8290.CD-18-0804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310008PMC
December 2018

Differential Sensitivity Analysis for Resistant Malignancies (DISARM) Identifies Common Candidate Therapies across Platinum-Resistant Cancers.

Clin Cancer Res 2019 01 26;25(1):346-357. Epub 2018 Sep 26.

Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Despite a growing arsenal of approved drugs, therapeutic resistance remains a formidable and, often, insurmountable challenge in cancer treatment. The mechanisms underlying therapeutic resistance remain largely unresolved and, thus, examples of effective combinatorial or sequential strategies to combat resistance are rare. Here, we present Differential Sensitivity Analysis for Resistant Malignancies (DISARM), a novel, integrated drug screen analysis tool designed to address this dilemma.

Experimental Design: DISARM, a software package and web-based application, analyzes drug response data to prioritize candidate therapies for models with resistance to a reference drug and to assess whether response to a reference drug can be utilized to predict future response to other agents. Using cisplatin as our reference drug, we applied DISARM to models from nine cancers commonly treated with first-line platinum chemotherapy including recalcitrant malignancies such as small cell lung cancer (SCLC) and pancreatic adenocarcinoma (PAAD).

Results: In cisplatin-resistant models, DISARM identified novel candidates including multiple inhibitors of PI3K, MEK, and BCL-2, among other classes, across unrelated malignancies. Additionally, DISARM facilitated the selection of predictive biomarkers of response and identification of unique molecular subtypes, such as contrasting ASCL1-low/cMYC-high SCLC targetable by AURKA inhibitors and ASCL1-high/cMYC-low SCLC targetable by BCL-2 inhibitors. Utilizing these predictions, we assessed several of DISARM's top candidates, including inhibitors of AURKA, BCL-2, and HSP90, to confirm their activity in cisplatin-resistant SCLC models.

Conclusions: DISARM represents the first validated tool to analyze large-scale drug response data to statistically optimize candidate drug and biomarker selection aimed at overcoming candidate drug resistance.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320267PMC
January 2019

CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade.

Cancer Discov 2018 09 16;8(9):1156-1175. Epub 2018 Jul 16.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. and studies demonstrate that CD38 inhibits CD8 T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment. CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8 T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-1033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205194PMC
September 2018

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas.

Cell Rep 2018 04;23(1):194-212.e6

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.
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http://dx.doi.org/10.1016/j.celrep.2018.03.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002769PMC
April 2018

Targeting DNA damage repair in small cell lung cancer and the biomarker landscape.

Transl Lung Cancer Res 2018 Feb;7(1):50-68

Department of Thoracic and Head & Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

Small cell lung cancer (SCLC) is an aggressive malignancy that accounts for 14% of all lung cancer diagnoses. Despite decades of active research, treatment options for SCLC are limited and resistance to the few Food and Drug Administration (FDA) approved therapies develops rapidly. With no approved targeted agents to date, new therapeutic strategies are desperately needed. SCLC is characterized by high mutation burden, ubiquitous loss of TP53 and RB1, mutually exclusive amplification of MYC family members, thereby, high genomic instability. Studies in the past few years have demonstrated the potential of targeting the DNA damage response (DDR) pathway as a promising therapeutic strategy for SCLC. Inhibitors targeting DDR proteins have shown promise in preclinical models, and are under clinical investigation as single agents and in combination with cytotoxic therapies. Recent efforts to expand the therapeutic arsenal toward SCLC have focused in part on immune checkpoint inhibitors, such as agents targeting the receptor-ligand pair programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). Clinical trials have confirmed activity of these agents in extensive stage (ES)-SCLC. However, while several patients had dramatic responses, overall response rates to immune checkpoint blockade (ICB) remain poor. As a result, there is an urgent need to develop rational combination therapies to enhance response rates to immunotherapy in SCLC. Identification of predictive biomarkers for patient stratification, identifying effective combinations to overcome adaptive resistance to DDR-targeted therapies and identifying strategies to enhance response to immunotherapy are areas of active investigation in SCLC.
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http://dx.doi.org/10.21037/tlcr.2018.02.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835589PMC
February 2018

Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer.

Oncotarget 2017 Apr;8(17):28575-28587

Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Small cell lung cancer (SCLC) is one of the most aggressive forms of cancer, with a 5-year survival <7%. A major barrier to progress is the absence of predictive biomarkers for chemotherapy and novel targeted agents such as PARP inhibitors. Using a high-throughput, integrated proteomic, transcriptomic, and genomic analysis of SCLC patient-derived xenografts (PDXs) and profiled cell lines, we identified biomarkers of drug sensitivity and determined their prevalence in patient tumors. In contrast to breast and ovarian cancer, PARP inhibitor response was not associated with mutations in homologous recombination (HR) genes (e.g., BRCA1/2) or HRD scores. Instead, we found several proteomic markers that predicted PDX response, including high levels of SLFN11 and E-cadherin and low ATM. SLFN11 and E-cadherin were also significantly associated with in vitro sensitivity to cisplatin and topoisomerase1/2 inhibitors (all commonly used in SCLC). Treatment with cisplatin or PARP inhibitors downregulated SLFN11 and E-cadherin, possibly explaining the rapid development of therapeutic resistance in SCLC. Supporting their functional role, silencing SLFN11 reduced in vitro sensitivity and drug-induced DNA damage; whereas ATM knockdown or pharmacologic inhibition enhanced sensitivity. Notably, SCLC with mesenchymal phenotypes (i.e., loss of E-cadherin and high epithelial-to-mesenchymal transition (EMT) signature scores) displayed striking alterations in expression of miR200 family and key SCLC genes (e.g., NEUROD1, ASCL1, ALDH1A1, MYCL1). Thus, SLFN11, EMT, and ATM mediate therapeutic response in SCLC and warrant further clinical investigation as predictive biomarkers.
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http://dx.doi.org/10.18632/oncotarget.15338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438673PMC
April 2017

Giving AXL the axe: targeting AXL in human malignancy.

Br J Cancer 2017 Feb 10;116(4):415-423. Epub 2017 Jan 10.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.

The receptor tyrosine kinase AXL, activated by a complex interaction between its ligand growth arrest-specific protein 6 and phosphatidylserine, regulates various vital cellular processes, including proliferation, survival, motility, and immunologic response. Although not implicated as an oncogenic driver itself, AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is overexpressed in several haematologic and solid malignancies, including acute myeloid leukaemia, non-small cell lung cancer, gastric and colorectal adenocarcinomas, and breast and prostate cancers. In the context of malignancy, evidence suggests that AXL overexpression drives wide-ranging processes, including epithelial to mesenchymal transition, tumour angiogenesis, resistance to chemotherapeutic and targeted agents, and decreased antitumor immune response. As a result, AXL is an attractive candidate not only as a prognostic biomarker in malignancy but also as a target for anticancer therapies. Several AXL inhibitors are currently in preclinical and clinical development. This article reviews the structure, regulation, and function of AXL; the role of AXL in the tumour microenvironment; the development of AXL as a therapeutic target; and areas of ongoing and future investigation.
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http://dx.doi.org/10.1038/bjc.2016.428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318970PMC
February 2017

Thymoma complicated by acquired amegakaryocytic thrombocytopenia and pure red cell aplasia.

J Natl Compr Canc Netw 2014 Nov;12(11):1505-9

From the Department of Medicine, University of Texas Health Science Center; and the Department of Thoracic/Head and Neck Medical Oncology, Department of Hematopathology, and Section of Thrombosis & Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Although the association of pure red cell aplasia (PRCA) and aplastic anemia with thymoma is well-known, acquired amegakaryocytic thrombocytopenia (AAMT) is not a recognized paraneoplastic manifestation of thymoma. This report discusses a patient with recurrent thymoma complicated by myasthenia gravis, PRCA, and AAMT. Both PRCA and AAMT are diagnosed after a thymoma recurrence, 11 years after complete resection of the initial tumor and 9 months after chemotherapy for the relapsed disease. Both PRCA and AAMT responded to immunosuppression with cyclosporine, corticosteroid, and an abbreviated course of antithymocyte globulin, achieving a very good erythroid response and a complete remission for AAMT, suggesting that AAMT, although extremely rare, can be an immune-mediated paraneoplastic manifestation of thymoma.
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http://dx.doi.org/10.6004/jnccn.2014.0149DOI Listing
November 2014

Diverse functions for the semaphorin receptor PlexinD1 in development and disease.

Dev Biol 2011 Jan 27;349(1):1-19. Epub 2010 Sep 27.

Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, 540 First Avenue, 4th floor, lab 14, New York, NY 10016, USA.

Plexins are a family of single-pass transmembrane proteins that serve as cell surface receptors for Semaphorins during the embryonic development of animals. Semaphorin-Plexin signaling is critical for many cellular aspects of organogenesis, including cell migration, proliferation and survival. Until recently, little was known about the function of PlexinD1, the sole member of the vertebrate-specific PlexinD (PlxnD1) subfamily. Here we review novel findings about PlxnD1's roles in the development of the cardiovascular, nervous and immune systems and salivary gland branching morphogenesis and discuss new insights concerning the molecular mechanisms of PlxnD1 activity.
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http://dx.doi.org/10.1016/j.ydbio.2010.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993764PMC
January 2011
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