Publications by authors named "Timothy F Burns"

50 Publications

Syngeneic tobacco carcinogen-induced mouse lung adenocarcinoma model exhibits PD-L1 expression and high tumor mutational burden.

JCI Insight 2021 Feb 8;6(3). Epub 2021 Feb 8.

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Human lung adenocarcinoma (LUAD) in current or former smokers exhibits a high tumor mutational burden (TMB) and distinct mutational signatures. Syngeneic mouse models of clinically relevant smoking-related LUAD are lacking. We established and characterized a tobacco-associated, transplantable murine LUAD cell line, designated FVBW-17, from a LUAD induced by the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone in the FVB/N mouse strain. Whole-exome sequencing of FVBW-17 cells identified tobacco-associated KrasG12D and Trp53 mutations and a similar mutation profile to that of classic alkylating agents with a TMB greater than 500. FVBW-17 cells transplanted subcutaneously, via tail vein, and orthotopically generated tumors that were histologically similar to human LUAD in FVB/N mice. FVBW-17 tumors expressed programmed death ligand 1 (PD-L1), were infiltrated with CD8+ T cells, and were responsive to anti-PD-L1 therapy. FVBW-17 cells were also engineered to express green fluorescent protein and luciferase to facilitate detection and quantification of tumor growth. Distant metastases to lung, spleen, liver, and kidney were observed from subcutaneously transplanted tumors. This potentially novel cell line is a robust representation of human smoking-related LUAD biology and provides a much needed preclinical model in which to test promising new agents and combinations, including immune-based therapies.
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http://dx.doi.org/10.1172/jci.insight.145307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934870PMC
February 2021

Targeting -Mutant Non-Small-Cell Lung Cancer: One Mutation at a Time, With a Focus on Mutations.

J Clin Oncol 2020 12 26;38(35):4208-4218. Epub 2020 Oct 26.

Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne University, Switzerland.

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http://dx.doi.org/10.1200/JCO.20.00744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723684PMC
December 2020

KRAS Inhibition with Sotorasib in Advanced Solid Tumors.

N Engl J Med 2020 09 20;383(13):1207-1217. Epub 2020 Sep 20.

From the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston (D.S.H., F.M.-B.); the Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), the University of California, San Francisco, San Francisco (P.N.M.), and Amgen, Thousand Oaks (H.H., J.N., G.N., J.K., B.E.H., J.C., J.R.L., G.F.) - all in California; Duke University Medical Center, Durham, NC (J.H.S.); Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Melbourne, VIC (J.D.), Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA (T.J.P.), and Scientia Clinical Research, Randwick, NSW (J.C. Kuo) - all in Australia; the Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis (G.A.D.); Dana-Farber Cancer Institute, Harvard Medical School, Boston (G.I.S.); the Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A.S.); Fox Chase Cancer Center, Philadelphia (C.S.D.); the University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh (T.F.B.); Seoul National University College of Medicine (Y.-J.B.), Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), and the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine (T.W.K.) - all in Seoul, South Korea; Roswell Park Cancer Institute, Buffalo (G.K.D.), and Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (P.L., B.T.L.) - all in New York; the University of Michigan, Ann Arbor (J.C. Krauss); the Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan (Y.K.); the Department of Medicine, Division of Oncology, University of Washington, Seattle (A.L.C.); Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille, France (F.B.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis (R.G.).

Background: No therapies for targeting mutations in cancer have been approved. The p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS.

Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.

Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
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http://dx.doi.org/10.1056/NEJMoa1917239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571518PMC
September 2020

Combined Modality Treatment With Brentuximab Vedotin and Radiation Therapy for Primary Cutaneous Anaplastic Large Cell Lymphoma: A Case Report.

J Hematol 2019 Sep 30;8(3):132-136. Epub 2019 Sep 30.

Department of Medicine, Division of Medical Oncology and Hematology, Mayo Clinic Health System, 1221 Whipple St., Eau Claire, WI, 54703, USA.

Primary cutaneous anaplastic large cell lymphoma (pcALCL) is a rare form of non-Hodgkins lymphoma. Current frontline treatments for pcALCL include surgical resection, anthracycline-based chemotherapy, and/or radiation therapy (RT) depending on disease severity. While brentuximab vedotin (BV) has been used for refractory/relapsed cases, it recently received Food and Drug Administration (FDA) approval for use in combination with chemotherapy for peripheral T-cell lymphomas. In this case report, we utilized a combined modality therapy of RT and BV for a limited stage aggressive pcALCL presentation for which routine management is contraindicated. A 59-year-old man with a history of peripheral vascular disease (PVD) presented with an aggressive pcALCL involving the left inferior eyelid and small ipsilateral level II hypermetabolic lymph nodes at stage IIE. Due to the patient's history of PVD, the tumor's rapid growth, possible lymph node involvement, and eye proximity, BV was chosen as the initial chemotherapy treatment followed by RT. Complete metabolic resolution of the primary cutaneous lesion and lymphadenopathy was reached after BV treatment alone; complete clinical response of the primary tumor was reached following radiation therapy. Relapse occurred within 7 months. Salvage cyclophosphamide, vincristine, etoposide, and prednisone were not effective. Retreatment with BV + RT is currently being used to treat the new lesions. Our case illustrates that a combination of BV and RT can be a safe and effective initial treatment in patients with limited stage pcALCL who cannot tolerate anthracycline-based chemotherapy. Our patient had a complete response but ultimately relapsed; thus larger clinical trials are needed to better understand early-stage disease.
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http://dx.doi.org/10.14740/jh534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153663PMC
September 2019

Is the game over for PD-1 inhibitors in mutant non-small cell lung cancer?

Transl Lung Cancer Res 2019 Dec;8(Suppl 4):S339-S342

Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.

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http://dx.doi.org/10.21037/tlcr.2019.04.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987364PMC
December 2019

Outcomes of patients with limited-stage aggressive large B-cell lymphoma with high-risk cytogenetics.

Blood Adv 2020 01;4(2):253-262

Roswell Park Comprehensive Cancer Center, Buffalo, NY.

There is a paucity of data regarding outcomes and response to standard therapy in patients with limited-stage (LS) agressive B-cell lymphoma (LS-ABCL) who harbor MYC rearrangement (MYC-R) with or without BCL2 and/or BCL6 rearrangements. We conducted a multicenter retrospective study of MYC-R LS-ABCL patients who received either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or more intensive immunochemotherapy (IIC) plus or minus consolidative involved-field radiation therapy (IFRT). One hundred four patients from 15 academic centers were included. Forty four patients (42%) received R-CHOP, of whom 52% had IFRT. Sixty patients (58%) received IIC, of whom 40% had IFRT. Overall response rate was 91% (84% complete response [CR]; 7% partial response). Patients with double-hit lymphoma (DHL; n = 40) had a lower CR rate compared with patients with MYC-R only (75% vs 98%; P = .003). CR rate was higher in the IFRT vs no-IFRT group (98% vs 72%; P < .001). Median follow-up was 3.2 years; 2-year progression-free survival (PFS) and overal survival (OS) were 78% and 86% for the entire cohort, and 74% and 81% for the DHL patients, respectively. PFS and OS were similar across treatment groups (IFRT vs no IFRT, R-CHOP vs IIC) in the entire cohort and in DHL patients. Our data provide a historical benchmark for MYC-R LS-ABCL and LS-DHL patients and show that outcomes for this population may be better than previously recognized. There was no benefit of using IIC over R-CHOP in patients with MYC-R LS-ABCL and LS-DHL.
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http://dx.doi.org/10.1182/bloodadvances.2019000875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988401PMC
January 2020

Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer.

Lung Cancer 2020 01 4;139:60-67. Epub 2019 Nov 4.

University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. Electronic address:

Objectives: KRAS mutations, which occur in approximately 25% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either TP53 or CDKN2A (INK4A/ARF) loci are sensitive to focal adhesion kinase (FAK) inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK.

Materials And Methods: Patients with previously treated advanced KRAS mutant NSCLC were prospectively assigned to one of four molecularly defined cohorts based on the presence or absence of TP53 or CDKN2A alterations and received treatment with defactinib 400 mg orally BID until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at 12 weeks.

Results: Fifty-five patients were enrolled. Mean age was 62 years; 51% were female. The median number of prior lines of therapy was 4 (range 1-8). Fifteen (28%) patients met the 12-week PFS endpoint, with one patient achieving a partial response. Median PFS was 45 days. Clinical efficacy did not correlate with TP53 or CDKN2A status. The most common adverse events were fatigue, gastrointestinal, and increased bilirubin, and were generally grade 1 or 2 in severity.

Conclusion: In heavily pretreated patients with KRAS mutant NSCLC, defactinib monotherapy demonstrated modest clinical activity. Efficacy was not associated with TP53 and CDKN2A status. Defactinib was generally well tolerated.
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http://dx.doi.org/10.1016/j.lungcan.2019.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942685PMC
January 2020

The estrogen pathway as a modulator of response to immunotherapy.

Immunotherapy 2019 09 30;11(13):1161-1176. Epub 2019 Jul 30.

Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.

Lung cancer is the leading cause of cancer deaths worldwide, with a 5-year survival rate of about 18%. Thus, there is a great need for novel therapeutic approaches to treat non-small-cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) have improved outcomes for a subset of patients, especially those with high programmed death-ligand 1 expression and/or high tumor mutational burden, but have failed in the majority of patients. Increasing evidence suggests that the estrogen signaling pathway may be a therapeutic target in metastatic NSCLC and that the estrogen pathway may play a role in sex-based responses to ICIs. This report will review the epidemiologic, preclinical and clinical data on the estrogen pathway in NSCLC, its implications in sex-based responses to ICIs and the potential use of antiestrogen therapy in combination with ICIs.
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http://dx.doi.org/10.2217/imt-2019-0024DOI Listing
September 2019

SNAIL is induced by tamoxifen and leads to growth inhibition in invasive lobular breast carcinoma.

Breast Cancer Res Treat 2019 Jun 23;175(2):327-337. Epub 2019 Feb 23.

Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.

Purpose: Invasive lobular carcinoma (ILC) is a histological subtype of breast cancer that is predominantly estrogen receptor alpha (ER)-positive (+) and is thus treated with endocrine therapies. Herein, we sought to understand the molecular underpinnings of the 4-hydroxytamoxifen (4OHT) resistance in ILC by assessing the potential role of the epithelial-to-mesenchymal transition transcription factor (EMT-TF) SNAIL (SNAI1).

Methods: Using a series of breast cancer cell lines, we measured the basal, estrogen and 4OHT-induced expression of SNAIL and other EMT-TF family members by quantitative reverse transcription-polymerase chain reaction and immunoblotting. Chromatin immunoprecipitation experiments were performed to assess ER binding to the SNAIL promoter. Cell proliferation, cell cycle and apoptosis were assessed in 2D cultures. 3D growth was assessed in Matrigel and Collagen I cultures.

Results: Estrogen and 4OHT induced SNAIL expression, but not that of the other EMT-TF family members SLUG (SNAI2) and SMUC (SNAI3), with the 4OHT effect being specific to the lobular but not the ductal subtype. We observed estrogen and 4OHT-induced ER recruitment to the SNAI1 promoter and high endogenous basal levels of SNAIL and several EMT-TFs in ILC cell lines. While SNAIL knockdown had a minor impact on the 4OHT partial agonism in estrogen-depleted conditions, it led to a surprising increase in cell proliferation in full serum. In complementary experiments, inducible SNAI1 overexpression caused decreased proliferation, associated with a cell cycle arrest in G/G. Additionally, apoptosis was observed in BCK4 cells.

Conclusion: These data suggest a previously unrecognized role for SNAIL in ILC, substantiating a context-dependent behavior for this EMT-TF.
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http://dx.doi.org/10.1007/s10549-019-05161-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625318PMC
June 2019

TWIST1 regulation of circRNA: a novel mechanism to promote epithelial-mesenchymal transition in hepatocellular carcinoma.

Noncoding RNA Investig 2018 Dec 19;2. Epub 2018 Dec 19.

Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.

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http://dx.doi.org/10.21037/ncri.2018.12.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363344PMC
December 2018

Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era.

J Clin Oncol 2019 02 7;37(6):471-480. Epub 2019 Jan 7.

1 Fox Chase Cancer Center, Philadelphia, PA.

Purpose: Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger.

Patients And Methods: We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed.

Results: Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2).

Conclusion: In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.
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http://dx.doi.org/10.1200/JCO.18.00690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554677PMC
February 2019

Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer.

Oncogene 2019 01 31;38(5):656-670. Epub 2018 Aug 31.

Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.

Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) have significantly benefited from the use of EGFR tyrosine kinase inhibitors (TKIs). However, long-term efficacy of these therapies is limited due to de novo resistance (~30%) as well as acquired resistance. Epithelial-mesenchymal transition transcription factors (EMT-TFs), have been identified as drivers of EMT-mediated resistance to EGFR TKIs, however, strategies to target EMT-TFs are lacking. As the third generation EGFR TKI, osimertinib, has now been adopted in the first-line setting, the frequency of T790M mutations will significantly decrease in the acquired resistance setting. Previously less common mechanisms of acquired resistance to first generation EGFR TKIs including EMT are now being observed at an increased frequency after osimertinib. Importantly, there are no other FDA approved targeted therapies after progression on osimertinib. Here, we investigated a novel strategy to overcome EGFR TKI resistance through targeting the EMT-TF, TWIST1, in EGFR-mutant NSCLC. We demonstrated that genetic silencing of TWIST1 or treatment with the TWIST1 inhibitor, harmine, resulted in growth inhibition and apoptosis in EGFR-mutant NSCLC. TWIST1 overexpression resulted in erlotinib and osimertinib resistance in EGFR-mutant NSCLC cells. Conversely, genetic and pharmacological inhibition of TWIST1 in EGFR TKI-resistant EGFR-mutant cells increased sensitivity to EGFR TKIs. TWIST1-mediated EGFR TKI resistance was due in part to TWIST1 suppression of transcription of the pro-apoptotic BH3-only gene, BCL2L11 (BIM), by directly binding to BCL2L11 intronic regions and promoter. As such, pan-BCL2 inhibitor treatment overcame TWIST1-mediated EGFR TKI resistance and were more effective in the setting of TWIST1 overexpression. Finally, in a mouse model of autochthonous EGFR-mutant lung cancer, Twist1 overexpression resulted in erlotinib resistance and suppression of erlotinib-induced apoptosis. These studies establish TWIST1 as a driver of resistance to EGFR TKIs and provide rationale for use of TWIST1 inhibitors or BCL2 inhibitors as means to overcome EMT-mediated resistance to EGFR TKIs.
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http://dx.doi.org/10.1038/s41388-018-0482-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358506PMC
January 2019

Cytogenetically cryptic insertion of PML segment into RARA on chromosome 17q resulting PML-RARA fusion in acute promyelocytic leukemia.

Ann Hematol 2019 Jan 20;98(1):211-213. Epub 2018 Jul 20.

Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center and Geisel School of Medicine Dartmouth College, Lebanon, NH, USA.

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http://dx.doi.org/10.1007/s00277-018-3399-1DOI Listing
January 2019

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

Haematologica 2018 09 7;103(9):1511-1517. Epub 2018 Jun 7.

Cardinal Health, Dublin, OH, USA.

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated , 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.
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http://dx.doi.org/10.3324/haematol.2018.193615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119152PMC
September 2018

HSP90 inhibition targets autophagy and induces a CASP9-dependent resistance mechanism in NSCLC.

Autophagy 2018 21;14(6):958-971. Epub 2018 Mar 21.

a Department of Pathology , University of Pittsburgh School of Medicine and The University of Pittsburgh Cancer Institute , Pittsburgh , PA , USA.

Macroautophagy/autophagy has emerged as a resistance mechanism to anticancer drug treatments that induce metabolic stress. Certain tumors, including a subset of KRAS-mutant NSCLCs have been shown to be addicted to autophagy, and potentially vulnerable to autophagy inhibition. Currently, autophagy inhibition is being tested in the clinic as a therapeutic component for tumors that utilize this degradation process as a drug resistance mechanism. The current study provides evidence that HSP90 (heat shock protein 90) inhibition diminishes the expression of ATG7, thereby impeding the cellular capability of mounting an effective autophagic response in NSCLC cells. Additionally, an elevation in the expression level of CASP9 (caspase 9) prodomain in KRAS-mutant NSCLC cells surviving HSP90 inhibition appears to serve as a cell survival mechanism. Initial characterization of this survival mechanism suggests that the altered expression of CASP9 is mainly ATG7 independent; it does not involve the apoptotic activity of CASP9; and it localizes to a late endosomal and pre-lysosomal phase of the degradation cascade. HSP90 inhibitors are identified here as a pharmacological approach for targeting autophagy via destabilization of ATG7, while an induced expression of CASP9, but not its apoptotic activity, is identified as a resistance mechanism to the cellular stress brought about by HSP90 inhibition.
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http://dx.doi.org/10.1080/15548627.2018.1434471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103412PMC
October 2019

Caveolin-1 promotes the tumor suppressor properties of oncogene-induced cellular senescence.

J Biol Chem 2018 02 15;293(5):1794-1809. Epub 2017 Dec 15.

From the Department of Pharmacology and Chemical Biology,

Oncogene-induced senescence (OIS) is considered a powerful tumor suppressor mechanism. Caveolin-1 acts as a scaffolding protein to functionally regulate signaling molecules. We demonstrate that a lack of caveolin-1 expression inhibits oncogenic K-Ras (K-Ras)-induced premature senescence in mouse embryonic fibroblasts and normal human bronchial epithelial cells. Oncogenic K-Ras induces senescence by limiting the detoxification function of MTH1. We found that K-Ras promotes the interaction of caveolin-1 with MTH1, which results in inhibition of MTH1 activity. Lung cancer cells expressing oncogenic K-Ras have bypassed the senescence barrier. Interestingly, overexpression of caveolin-1 restores cellular senescence in both A549 and H460 lung cancer cells and inhibits their transformed phenotype. In support of these findings, our data demonstrate that overexpression of oncogenic K-Ras (K-Ras) induces cellular senescence in the lung of wildtype but not caveolin-1-null mice. A lack of K-Ras-induced premature senescence in caveolin-1-null mice results in the formation of more abundant lung tumors. Consistent with these data, caveolin-1-null mice overexpressing K-Ras display accelerated mortality. Finally, our animal data were supported by human sample analysis in which we show that caveolin-1 expression is dramatically down-regulated in lung adenocarcinomas from lung cancer patients, both at the mRNA and protein levels, and that low caveolin-1 expression is associated with poor survival. Together, our data suggest that lung cancer cells escape oncogene-induced premature senescence through down-regulation of caveolin-1 expression to progress from premalignant lesions to cancer.
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http://dx.doi.org/10.1074/jbc.M117.815902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798308PMC
February 2018

Wnt/β-Catenin Pathway Activation Mediates Adaptive Resistance to BRAF Inhibition in Colorectal Cancer.

Mol Cancer Ther 2018 04 22;17(4):806-813. Epub 2017 Nov 22.

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

One of the most encouraging developments in oncology has been the success of BRAF inhibitors in -mutant melanoma. However, in contrast to its striking efficacy in -mutant melanomas, BRAF inhibitor monotherapy is ineffective in -mutant colorectal cancer. Although many studies on BRAF inhibitor resistance in colorectal cancer have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on colorectal cancer resistance to BRAF inhibition. We found that treatment with BRAF inhibitors (both current and next-generation BRAF inhibitors) upregulated the Wnt/β-catenin pathway in -mutant colorectal cancer cell lines through activating the cytoplasmic tyrosine kinase focal adhesion kinase (FAK). The results showed that FAK activation upon BRAF inhibitor treatment did not require EGFR or ERK1/2 activation, implying that BRAF inhibitor treatment-induced hyperactivation of Wnt signaling is "pathway reactivation"-independent. BRAF inhibition-induced Wnt pathway activation was further validated in preclinical models of -mutant colorectal cancer, including cell line xenograft model and a patient-derived xenograft model. Combined inhibition of BRAF/Wnt pathways or BRAF/FAK pathways exerted strong synergistic antitumor effects in cell culture model and mouse xenograft model. Overall, the current study has identified activation of the Wnt/β-catenin pathway as a novel fundamental cause of colon cancer resistance to BRAF inhibition. Our results suggest that although complete vertical pathway blockade is pivotal for effective and durable control of -mutant colorectal cancer, cotargeting parallel adaptive signaling-the Wnt/β-catenin pathway-is also essential. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882543PMC
April 2018

First-Line Osimertinib in Patients with Treatment-Naive Somatic or Germline EGFR T790M-Mutant Metastatic NSCLC.

J Thorac Oncol 2018 01 5;13(1):e3-e5. Epub 2017 Oct 5.

University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2017.09.1963DOI Listing
January 2018

Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach.

Int J Mol Sci 2017 Sep 15;18(9). Epub 2017 Sep 15.

Department of Medicine, Division of Hematology Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Heat shock proteins (HSPs) are a large family of chaperones that are involved in protein folding and maturation of a variety of "client" proteins protecting them from degradation, oxidative stress, hypoxia, and thermal stress. Hence, they are significant regulators of cellular proliferation, differentiation and strongly implicated in the molecular orchestration of cancer development and progression as many of their clients are well established oncoproteins in multiple tumor types. Interestingly, tumor cells are more HSP chaperonage-dependent than normal cells for proliferation and survival because the oncoproteins in cancer cells are often misfolded and require augmented chaperonage activity for correction. This led to the development of several inhibitors of HSP90 and other HSPs that have shown promise both preclinically and clinically in the treatment of cancer. In this article, we comprehensively review the roles of some of the important HSPs in cancer, and how targeting them could be efficacious, especially when traditional cancer therapies fail.
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http://dx.doi.org/10.3390/ijms18091978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618627PMC
September 2017

TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression.

Clin Cancer Res 2017 Dec 12;23(23):7324-7332. Epub 2017 Sep 12.

University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCCs), raising the possibility of an anti-apoptotic role in malignant cells. This study investigated this using a multimodal, translational investigation. Combination of (i) HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression (ii) studies assessing similar outcomes, and (iii) molecular and staining analysis of human HNSCC samples. TMEM16A expression was found to correlate with greater tumor size, increased Erk 1/2 activity, less Bim expression, and less apoptotic activity overall in human HNSCC. These findings were corroborated in subsequent and studies and expanded to include a cisplatin-resistant phenotype with TMEM16A overexpression. A cohort of 41 patients with laryngeal cancer demonstrated that cases that recurred after chemoradiation failure were associated with a greater TMEM16A overexpression rate than HNSCC that did not recur. Ultimately, this study implicates TMEM16A as a contributor to tumor progression by limiting apoptosis and as a potential biomarker of more aggressive disease. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898434PMC
December 2017

A First-in-Class TWIST1 Inhibitor with Activity in Oncogene-Driven Lung Cancer.

Mol Cancer Res 2017 12 29;15(12):1764-1776. Epub 2017 Aug 29.

Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.

TWIST1, an epithelial-mesenchymal transition (EMT) transcription factor, is critical for oncogene-driven non-small cell lung cancer (NSCLC) tumorigenesis. Given the potential of TWIST1 as a therapeutic target, a chemical-bioinformatic approach using connectivity mapping (CMAP) analysis was used to identify TWIST1 inhibitors. Characterization of the top ranked candidates from the unbiased screen revealed that harmine, a harmala alkaloid, inhibited multiple TWIST1 functions, including single-cell dissemination, suppression of normal branching in 3D epithelial culture, and proliferation of oncogene driver-defined NSCLC cells. Harmine treatment phenocopied genetic loss of by inducing oncogene-induced senescence or apoptosis. Mechanistic investigation revealed that harmine targeted the TWIST1 pathway through its promotion of TWIST1 protein degradation. As dimerization is critical for TWIST1 function and stability, the effect of harmine on specific TWIST1 dimers was examined. TWIST1 and its dimer partners, the E2A proteins, which were found to be required for TWIST1-mediated functions, regulated the stability of the other heterodimeric partner posttranslationally. Harmine preferentially promoted degradation of the TWIST1-E2A heterodimer compared with the TWIST-TWIST1 homodimer, and targeting the TWIST1-E2A heterodimer was required for harmine cytotoxicity. Finally, harmine had activity in both transgenic and patient-derived xenograft mouse models of -mutant NSCLC. These studies identified harmine as a first-in-class TWIST1 inhibitor with marked anti-tumor activity in oncogene-driven NSCLC including mutant, mutant and altered NSCLC. TWIST1 is required for oncogene-driven NSCLC tumorigenesis and EMT; thus, harmine and its analogues/derivatives represent a novel therapeutic strategy to treat oncogene-driven NSCLC as well as other solid tumor malignancies. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712248PMC
December 2017

Core Entrustable Professional Activities in Clinical Pharmacology for Entering Residency: Biologics.

J Clin Pharmacol 2017 08 14;57(8):947-955. Epub 2017 Jun 14.

The American College of Clinical Pharmacology, Rockville, MD, USA.

Biologicals are a rapidly expanding class of medications used in the treatment of many different conditions. This article reviews the common characteristics of this class and the requirements for safe and effective use in patients. Several vignettes are included to illustrate common challenges.
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http://dx.doi.org/10.1002/jcph.938DOI Listing
August 2017

Reactivation of the p90RSK-CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G-M Arrest and Mediates Acquired Resistance to Ganetespib in -Mutant NSCLC.

Mol Cancer Ther 2017 08 31;16(8):1658-1668. Epub 2017 May 31.

Department of Medicine, Division of Hematology Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

A subset of non-small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations, including the most frequently observed driver mutant which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Hsp90 inhibitors appeared to be a promising therapy for -mutant NSCLC; however, limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib, and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit. Here, we investigated the mechanism(s) of resistance to ganetespib and explored why the combination with docetaxel failed in the clinic. We have not only identified a critical role for the bypass of the G-M cell-cycle checkpoint as a mechanism of ganetespib resistance (GR) but have also found that GR leads to cross-resistance to docetaxel. Reactivation of p90RSK and its downstream target, CDC25C, was critical for GR and mediated the bypass of a G-M arrest. Overexpression of either p90RSK or CDC25C lead to bypass of G-M arrest and induced ganetespib resistance and Moreover, resistance was dependent on p90RSK/CDC25C signaling, as synthetic lethality to ERK1/2, p90RSK, or CDC25C inhibitors was observed. Importantly, the combination of ganetespib and p90RSK or CDC25C inhibitors was highly efficacious in parental cells. These studies provide a way forward for Hsp90 inhibitors through the development of novel rationally designed Hsp90 inhibitor combinations that may prevent or overcome resistance to Hsp90i. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544554PMC
August 2017

Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non-small cell lung cancer.

Cancer 2017 Aug 4;123(15):2936-2944. Epub 2017 May 4.

Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.

Background: Activation of the mesenchymal-epidermal transition factor (MET) tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was evaluated in patients with metastatic, previously treated non-small cell lung cancer.

Methods: In phase 1, a dose de-escalation design was adopted with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg daily. In phase 2, the disease control rate (DCR) (according to Response Evaluation Criteria in Solid Tumors) of the combination was evaluated using a Simon 2-stage design. The biomarkers examined included 10 plasma-circulating molecules associated with the EGFR and MET pathways.

Results: Without indications for de-escalation, the recommended phase 2 dose was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid progression (hazard ratio, 2.14; 95% CI, 1.48-3.08).

Conclusions: Combined rilotumumab and erlotinib had an acceptable safety profile, and the DCR met the prespecified criteria for success. In the EGFR WT group, the DCR exceeded published reports for erlotinib alone. High circulating levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 2017;123:2936-44. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517339PMC
August 2017

The next generation of immunotherapy: keeping lung cancer in check.

J Hematol Oncol 2017 04 24;10(1):87. Epub 2017 Apr 24.

University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Lung cancer is the deadliest malignancy with more cancer deaths per year than the next three cancers combined. Despite remarkable advances in targeted therapy, advanced lung cancer patients have not experienced a significant improvement in mortality. Lung cancer has been shown to be immunogenic and responsive to checkpoint blockade therapy. Checkpoint signals such as CTLA-4 and PD-1/PD-L1 dampen T cell activation and allow tumors to escape the adaptive immune response. Response rates in patients with pretreated, advanced NSCLC were much higher and more durable with PD-1 blockade therapy compared to standard-of-care, cytotoxic chemotherapy. Therefore, PD-1 inhibitors such as nivolumab and pembrolizumab were rapidly approved for both squamous and nonsquamous lung cancer in the pretreated population. The advent of these new therapies have revolutionized the treatment of lung cancer; however, the majority of NSCLC patients still do not respond to PD-1/PD-L1 inhibition leaving an unmet need for a large and growing population.Immunotherapy combinations with chemotherapy, radiation therapy, or novel immunomodulatory agents are currently being examined with the hope of achieving higher response rates and improving overall survival rate. Chemotherapy and radiation therapy has been theorized to increase the release of tumor antigen leading to increased responses with immunotherapy. However, cytotoxic chemotherapy and radiation therapy may also destroy actively proliferating T cells. The correct combination and order of therapy is under investigation. The majority of patients who do respond to immunotherapy have a durable response attributed to the effect of adaptive immune system's memory. Unfortunately, some patients' tumors do progress afterward and investigation of checkpoint blockade resistance is still nascent.This review will summarize the latest efficacy and safety data for early and advanced NSCLC in both the treatment-naïve and pretreated settings. The emerging role of immunotherapy for the treatment of small cell lung cancer and malignant mesothelioma will also be discussed.
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http://dx.doi.org/10.1186/s13045-017-0456-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402056PMC
April 2017

Pembrolizumab in the treatment of metastatic non-small-cell lung cancer: patient selection and perspectives.

Lung Cancer (Auckl) 2017 11;8:1-11. Epub 2017 Jan 11.

Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.

Lung cancer is the leading killer of both men and women in the US, and the 5-year survival remains poor. However, the approval of checkpoint blockade immunotherapy has shifted the treatment paradigm and provides hope for improved survival. The ability of non-small-cell lung cancer (NSCLC) to evade the host immune system can be overcome by agents such as pembrolizumab (MK-3475/lambrolizumab), which is a monoclonal antibody targeting the programmed death 1 (PD-1) receptor. In early studies, treatment with pembrolizumab led to dramatic and durable responses in select patients (PD-L1+ tumors). This remarkable efficacy lead to approval of pembrolizumab in the second-line setting as response rates were almost doubled compared to standard of care (SOC) chemotherapy. Most recently, data in the first-line setting from the KEYNOTE-024 study have redefined the SOC therapy for a selected subset of patients. In patients with ≥50% PD-L1+ tumors, pembrolizumab had a clear progression-free survival and overall survival benefit. Toxicity was mostly immune related and similar to checkpoint blockade toxicities observed in previous studies. The initial approval and subsequent studies of pembrolizumab required and utilized a companion diagnostic test, Dako's IHC 22C3, to assess PD-L1 status of patients. The evaluation and scoring system of this assay has been used by other companies as a reference to develop their own assays, which may complicate selection of patients. Finally, the impact of pembrolizumab in NSCLC is growing as evidenced by the numerous, ongoing trials open for combinations with chemotherapy, chemoradiation, other immunotherapeutics, immunomodulators, tyrosine kinase inhibitors, PI3K inhibitors, MEK inhibitors, hypomethylating agents, and histone deacetylase inhibitors. Further studies are also evaluating pembrolizumab in small-cell lung cancer and malignant pleural mesothelioma. This explosion of studies truly conveys the lack of therapeutic answers for lung cancer patients and the promise of pembrolizumab.
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http://dx.doi.org/10.2147/LCTT.S105678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342609PMC
January 2017

Acquired Resistance to the Hsp90 Inhibitor, Ganetespib, in Mutant NSCLC Is Mediated via Reactivation of the ERK-p90RSK-mTOR Signaling Network.

Mol Cancer Ther 2017 05 6;16(5):793-804. Epub 2017 Feb 6.

Department of Medicine, Division of Hematology Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

Approximately 25% of non-small cell lung cancer (NSCLC) patients have mutations, and no effective therapeutic strategy exists for these patients. The use of Hsp90 inhibitors in -mutant NSCLC appeared to be a promising approach, as these inhibitors target many KRAS downstream effectors; however, limited clinical efficacy has been observed due to resistance. Here, we examined the mechanism(s) of acquired resistance to the Hsp90 inhibitor, ganetespib, and identified novel and rationally devised Hsp90 inhibitor combinations, which may prevent and overcome resistance to Hsp90 inhibitors. We derived -mutant NSCLC ganetespib-resistant cell lines to identify the resistance mechanism(s) and identified hyperactivation of RAF/MEK/ERK/RSK and PI3K/AKT/mTOR pathways as key resistance mechanisms. Furthermore, we found that ganetespib-resistant cells are "addicted" to these pathways, as ganetespib resistance leads to synthetic lethality to a dual PI3K/mTOR, a PI3K, or an ERK inhibitor. Interestingly, the levels and activity of a key activator of the mTOR pathway and an ERK downstream target, p90 ribosomal S6 kinase (RSK), were also increased in the ganetespib-resistant cells. Genetic or pharmacologic inhibition of p90RSK in ganetespib-resistant cells restored sensitivity to ganetespib, whereas p90RSK overexpression induced ganetespib resistance in naïve cells, validating p90RSK as a mediator of resistance and a novel therapeutic target. Our studies offer a way forward for Hsp90 inhibitors through the rational design of Hsp90 inhibitor combinations that may prevent and/or overcome resistance to Hsp90 inhibitors, providing an effective therapeutic strategy for -mutant NSCLC. .
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418121PMC
May 2017

Paradoxical functions of ZEB1 in -mutant lung cancer: tumor suppressor and driver of therapeutic resistance.

J Thorac Dis 2016 Nov;8(11):E1528-E1531

Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA;; Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.

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http://dx.doi.org/10.21037/jtd.2016.11.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179406PMC
November 2016

HSP90 inhibitors in lung cancer: promise still unfulfilled.

Clin Adv Hematol Oncol 2016 May;14(5):346-56

University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

Despite recent advances in the treatment of lung cancer, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths in the United States and worldwide, with a 5-year survival rate of less than 17%. Analysis of the molecular drivers of NSCLC led to the recognition that NSCLC is a collection of distinct, molecularly driven neoplasms. Several subsets of NSCLC with clinical relevance to targeted therapies are defined based on alterations in EGFR, ALK, and other key oncogenic drivers. However, for many oncogenic drivers-such as mutant KRAS-targeted therapies are lacking. Heat shock protein 90 (HSP90) is an adenosine triphosphate (ATP)-dependent molecular chaperone that is critically required for the stability of its clientele, many of which are driver oncoproteins. Therefore, HSP90 inhibitors could prove to be an effective and alternate approach to treat patients with NSCLC that has a specific molecular background or that has acquired resistance to other drugs. Over the last 2 decades, several HSP90 inhibitors have been developed that produced promising preclinical and clinical results. The quest is far from over, however. In this review, we discuss the development and the preclinical and clinical profiles of some of the HSP90 inhibitors that may help to improve the targeted treatment of NSCLC.
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May 2016

Near complete response after single dose of nivolumab in patient with advanced heavily pre-treated KRAS mutant pulmonary adenocarcinoma.

Exp Hematol Oncol 2015 14;4:34. Epub 2015 Dec 14.

Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA USA ; Division of Hematology-Oncology, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Office: Suite 2.18e, Pittsburgh, PA 15232 USA.

The programmed death 1 (PD-1) receptor is expressed by activated T-cells and engaged by ligands PD-L1 and PD-L2 normally expressed by infiltrating immune cells in response to viral infection. The PD-1/PD-L1 axis is a negative inhibitory pathway that down-regulates T-cells but is also used by tumors to evade anti-tumor immunity. Antibodies targeting PD-1/PD-L1 axis are capable of restoring functional anti-tumor immunity and have demonstrated efficacy in a broad range of tumor types including non-small cell lung cancer in both squamous and adenocarcinoma histologies. Ongoing issues affecting clinical development of these agents include assessment of response, optimal duration of therapy in excellent responders, predictive biomarkers and mechanisms of resistance. In this report, we describe a patient with advanced KRAS mutant heavily pretreated pulmonary adenocarcinoma who developed an excellent response after a single-dose of nivolumab. Pre-treatment tumor was found to have moderate CD3 and PD-L1 positivity by immunohistochemical staining. Evaluation of exceptional responders and non-responders are critical to furthering our understanding of the mechanisms of action (and resistance) to these agents.
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http://dx.doi.org/10.1186/s40164-015-0029-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678465PMC
December 2015