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Functional analysis of MET exon 14 skipping alteration in cancer invasion and metastatic dissemination

Wang, Feng; Liu, Yang; Qiu, Wanglong; Shum, Elaine; Feng, Monica; Zhao, Dejian; Zheng, Deyou; Borczuk, Alain; Cheng, Haiying; Halmos, Balazs
MET exon 14 skipping alteration (MET∆14Ex) is an actionable oncogenic driver that occurs in 2-4% of non-small cell lung cancer (NSCLC) cases. The precise role of MET∆14Ex in tumor progression of NSCLC is poorly understood. Using multiple isogenic MET∆14Ex cell models established with CRISPR editing, we demonstrate that MET∆14Ex expression increases receptor kinase activity and downstream signaling by impairing receptor internalization and endocytic degradation, significantly boosting cell scatter, migration, and invasion capacity in vitro as well as metastasis in vivo. RNA sequencing analysis revealed that MET∆14Ex preferentially activates biological processes associated with cell movement, providing novel insights into its unique molecular mechanism of action. Activation of PI3K/Akt/Rac1 signaling and upregulation of multiple matrix metallopeptidases (MMPs) by MET∆14Ex induced cytoskeleton remodeling and extracellular matrix disassembly, which are critical functional pathways that facilitate cell invasion and metastasis. Therapeutically, MET inhibitors dramatically repressed MET∆14Ex-mediated tumor growth and metastasis in vivo, indicating potential therapeutic options for MET∆14Ex-altered NSCLC patients. These mechanistic insights into MET∆14Ex-mediated invasion and metastasis provide a deeper understanding of the role of MET∆14Ex in NSCLC.
PMID: 35078819
ISSN: 1538-7445
CID: 5154452

The Common Thread: A Case of Synchronous Lung Cancers and a Germline CHEK2 Mutation [Case Report]

Carey, Edward T; Ferreira, Virginia; Shum, Elaine; Zhou, Fang; Sabari, Joshua K
Patients with one form of cancer are at increased risk for another, and this is true for lung cancer, where synchronous primary lung cancers are an increasing multifaceted challenge.1,2 Here, we present the case of a middle age woman who was found to have bilateral lung masses. Biopsy and subsequent testing revealed unique synchronous lung adenocarcinomas, each with unique genetic signatures. Despite having two unique tumors, she was found to have CHEK2 mutations in both tumors and in germline testing. Because of this extensive testing that showed unique tumors, she was ultimately diagnosed with stage IIIb and IA2 lung cancers, and this changed her treatment options. Consideration of unique primary tumors leads to thorough diagnostics, which changed this patient's diagnosis, prognosis, and treatment. We hope this case raises awareness for multiple primary tumors, as well as CHEK2 as an important oncogene.
PMID: 34246541
ISSN: 1938-0690
CID: 4938102

Molecular cytology of the respiratory tract and pleura

Zhou, Fang; Shum, Elaine; Moreira, Andre L
There is growing evidence that molecular testing is feasible on all types of cytological preparation, which is fortunate as more diagnostic markers and biomarkers for targeted therapies are discovered for use in pulmonary and pleural malignancies. In this article we will discuss the pre-analytic, analytic, and post-analytic (interpretive) considerations for successful implementation of molecular tests for diagnostic and predictive markers in respiratory and pleural cytology. The vast majority of laboratories are familiar with, and have validated their molecular protocols for, formalin-fixed paraffin-embedded surgical specimens, which are not directly applicable to cytology specimens. Thus, rigorous validation must be performed for each type of fixative and cytology preparation before it is implemented in the clinical setting.
PMID: 34333812
ISSN: 1365-2303
CID: 4988462

The incidence and predictors of new brain metastases in patients with non-small cell lung cancer following discontinuation of systemic therapy

London, Dennis; Patel, Dev N; Donahue, Bernadine; Navarro, Ralph E; Gurewitz, Jason; Silverman, Joshua S; Sulman, Erik; Bernstein, Kenneth; Palermo, Amy; Golfinos, John G; Sabari, Joshua K; Shum, Elaine; Velcheti, Vamsidhar; Chachoua, Abraham; Kondziolka, Douglas
OBJECTIVE:Patients with non-small cell lung cancer (NSCLC) metastatic to the brain are living longer. The risk of new brain metastases when these patients stop systemic therapy is unknown. The authors hypothesized that the risk of new brain metastases remains constant for as long as patients are off systemic therapy. METHODS:A prospectively collected registry of patients undergoing radiosurgery for brain metastases was analyzed. Of 606 patients with NSCLC, 63 met the inclusion criteria of discontinuing systemic therapy for at least 90 days and undergoing active surveillance. The risk factors for the development of new tumors were determined using Cox proportional hazards and recurrent events models. RESULTS:The median duration to new brain metastases off systemic therapy was 16.0 months. The probability of developing an additional new tumor at 6, 12, and 18 months was 26%, 40%, and 53%, respectively. There were no additional new tumors 22 months after stopping therapy. Patients who discontinued therapy due to intolerance or progression of the disease and those with mutations in RAS or receptor tyrosine kinase (RTK) pathways (e.g., KRAS, EGFR) were more likely to develop new tumors (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.81, p = 2.5 × 10-3; HR 2.51, 95% CI 1.45-4.34, p = 9.8 × 10-4, respectively). CONCLUSIONS:The rate of new brain metastases from NSCLC in patients off systemic therapy decreases over time and is uncommon 2 years after cessation of cancer therapy. Patients who stop therapy due to toxicity or who have RAS or RTK pathway mutations have a higher rate of new metastases and should be followed more closely.
PMID: 34891140
ISSN: 1933-0693
CID: 5110502

Clinical benefit through Siglec-15 targeting with NC318 antibody in subjects with Siglec-15 positive advanced solid tumors [Meeting Abstract]

Shum, E; Myint, H; Shaik, J; Zhou, Q; Barbu, E; Morawski, A; Abukharma, H; Liu, L; Nelson, M; Zeidan, S; Cusumano, Z; Tolcher, A; Langermann, S; Gutierrez, M; Hamid, O
Background Siglec-15 (S15) is a member of the Siglec family of immunoglobulin superfamily proteins involved in immune regulation. NC318 is a first-in-class humanized IgG1k monoclonal antibody that blocks S15-mediated immune suppression. Methods The Phase 1 dose-escalation study was a classical 3 +3 design in 15 tumor types (n=49). Phase 2 (n=47) was conducted at 400 mg q2w in 4 tumor types. Inclusion criteria included subjects with advanced/metastatic solid tumors refractory or resistant to currently available therapies with a TPS PD-L1 score <50%. The median number of previous therapies was >=3, including checkpoint inhibitors (figure 1). Results NC318 was well tolerated with no novel immunologic or safety signals observed. Disease control rate amongst evaluable population (n=83) is 38% {1 CR, 3 PR and 28 SD (stable disease)}. Median duration of disease control is 24 weeks (16-48 weeks) amongst 20 subjects achieving a minimal 16- week duration of stable disease. Two NSCLC subjects (1CR and 1PR) are still on therapy over 2 years. We observed an increase in a soluble form of Siglec-15 (sS15) in all patients receiving NC318 treatment that was dose-dependent. sS15 serves as a pharmacodynamic marker for NC318 activity. PK/ PD modeling of NC318 from this Phase1/2 study using sS15 as a PD marker suggested increasing the dose of NC318 to 800 mg q1w to enhance overall exposure of NC318. Development of an S15 specific IHC assay allowed us to do posthoc analysis by immuno-histochemistry (IHC) from screening biopsies amongst subjects who showed disease control (CR, PR and SD) compared to subjects with progressive disease. S15 expression on tumor cell membrane was a predictor for stable disease, longer duration on therapy when compared to progressive disease {H score >= 1 (p=0.046), including NSCLC subjects}, as well as for progression-free survival (PFS) (figures 2 and 3). There was no correlation with the outcome whether PD-L1 was positive or negative. Together, development of a predictive indicator of S15 staining coupled with the NC318 PK/PD data, resulted in a protocol amendment to prospectively enroll subjects with Siglec-15+ adenocarcinoma lung, squamous H&N, and breast cancers at 800 mg q1w. Soluble S15, immunophenotyping, cytokine and chemokine levels and neutrophil-lymphocyte ratio will be presented at the meeting. Conclusions NC318 shows promising early evidence of disease control in subjects with Siglec-15 positive advanced or metastatic solid tumors in phase 1 & 2 studies, prompting evaluation of S15 expression as a predictive biomarker in the prospective study at 800mg q1w dosing
EMBASE:636986061
ISSN: 2051-1426
CID: 5138542

Preliminary clinical experience with XMAB20717, a PD-1 X CTLA-4 bispecific antibody, in patients with advanced solid tumors [Meeting Abstract]

Shum, E; Reilley, M; Najjar, Y; Daud, A; Thompson, J; Baranda, J; Harvey, R D; Shields, A; Cohen, E; Pant, S; Leidner, R; Mita, A; Cohen, R; Chmielowski, B; Stein, M; Hu-Lieskovan, S; Fleener, C; Ding, Y; Bao, L; Chollate, S; Shorr, J; Clynes, R; Hickingbottom, B
Background XmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, doseescalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options. Methods A maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST [1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDAapproved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety. Results As of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases >= 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade >= 3 immunotherapy-related adverse events in >= 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%). Conclusions Preliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer
EMBASE:636985411
ISSN: 2051-1426
CID: 5134952

TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation

Ho, Jessica Sook Yuin; Mok, Bobo Wing-Yee; Campisi, Laura; Jordan, Tristan; Yildiz, Soner; Parameswaran, Sreeja; Wayman, Joseph A; Gaudreault, Natasha N; Meekins, David A; Indran, Sabarish V; Morozov, Igor; Trujillo, Jessie D; Fstkchyan, Yesai S; Rathnasinghe, Raveen; Zhu, Zeyu; Zheng, Simin; Zhao, Nan; White, Kris; Ray-Jones, Helen; Malysheva, Valeriya; Thiecke, Michiel J; Lau, Siu-Ying; Liu, Honglian; Zhang, Anna Junxia; Lee, Andrew Chak-Yiu; Liu, Wen-Chun; Jangra, Sonia; Escalera, Alba; Aydillo, Teresa; Melo, Betsaida Salom; Guccione, Ernesto; Sebra, Robert; Shum, Elaine; Bakker, Jan; Kaufman, David A; Moreira, Andre L; Carossino, Mariano; Balasuriya, Udeni B R; Byun, Minji; Albrecht, Randy A; Schotsaert, Michael; Garcia-Sastre, Adolfo; Chanda, Sumit K; Miraldi, Emily R; Jeyasekharan, Anand D; TenOever, Benjamin R; Spivakov, Mikhail; Weirauch, Matthew T; Heinz, Sven; Chen, Honglin; Benner, Christopher; Richt, Juergen A; Marazzi, Ivan
The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.
PMID: 33836156
ISSN: 1097-4172
CID: 4840702

Entinostat plus pembrolizumab in patients with metastatic NSCLC previously treated with anti-PD-(L)1 therapy

Hellmann, Matthew D; Janne, Pasi A; Opyrchal, Mateusz; Hafez, Navid; Raez, Luis E; Gabrilovich, Dmitry I; Wang, Fang; Trepel, Jane B; Lee, Min-Jung; Yuno, Akira; Lee, Sunmin; Brouwer, Susan; Sankoh, Serap; Wang, Lei; Tamang, David; Schmidt, Emmett V; Meyers, Michael L; Ramalingam, Suresh S; Shum, Elaine; Ordentlich, Peter
PURPOSE/OBJECTIVE:New therapies are needed to treat immune checkpoint inhibitor-resistant non-small cell lung cancer (NSCLC) and identify biomarkers to personalize treatment. Epigenetic therapies, including histone deacetylase inhibitors, may synergize with programmed cell death-1 (PD-1)blockade to overcome resistance. We report outcomes in patients with anti-PD-(L)1-resistant/refractory NSCLC treated with pembrolizumab plus entinostat in ENCORE 601. EXPERIMENTAL DESIGN/METHODS:The expansion cohort of ENCORE 601 included patients with NSCLC who previously experienced disease progression with immune checkpoint inhibitors. The primary endpoint for the phase 2 expansion cohort is overall response rate (ORR); safety, tolerability, and exploratory endpoints are described. RESULTS:Of 76 treated patients,71 were evaluable for efficacy. irRECIST-assessed ORRwas 9.2%(95% CI: 3.8-18.1), which did not meet the prespecified threshold for positivity. Median DOR was 10.1 months(95% CI: 3.9-NE),PFS at 6 months was 22%, median PFS was 2.8 months(95% CI: 1.5-4.1),and median OS was11.7 months (95% CI: 7.6-13.4). Benefit was enriched among patients with high levels of circulating classical monocytes at baseline. Baseline tumor PD-L1 expression and IFNγgene expression were not associated with benefit. Treatment-related Grade ≥3 adverse events occurred in 41% of patients. CONCLUSIONS:In anti-PD-(L)1-experienced NSCLC patients, entinostat plus pembrolizumab did not achieve the primary response rate endpoint but provided a clinically meaningful benefit with objective response in 9% of patients. No new toxicities, including immune-related adverse events, were seen for either drug. Future studies will continue to evaluate the association of monocyte levels and response.
PMID: 33203644
ISSN: 1078-0432
CID: 4681412

Comparing Lung Cancer in Never Smokers and Ever Smokers in Asian or Asian American Patients Treated at a Tertiary Urban Public Hospital in New York [Meeting Abstract]

Kroening, G.; Sabari, J.; Velcheti, V.; Chachoua, A.; Wong, K.; Shum, E.
ISI:000709606500313
ISSN: 1556-0864
CID: 5074192

Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models

Yuin Ho, Jessica Sook; Wing-Yee Mok, Bobo; Campisi, Laura; Jordan, Tristan; Yildiz, Soner; Parameswaran, Sreeja; Wayman, Joseph A; Gaudreault, Natasha N; Meekins, David A; Indran, Sabarish V; Morozov, Igor; Trujillo, Jessie D; Fstkchyan, Yesai S; Rathnasinghe, Raveen; Zhu, Zeyu; Zheng, Simin; Zhao, Nan; White, Kris; Ray-Jones, Helen; Malysheva, Valeriya; Thiecke, Michiel J; Lau, Siu-Ying; Liu, Honglian; Junxia Zhang, Anna; Chak-Yiu Lee, Andrew; Liu, Wen-Chun; Aydillo, Teresa; Salom Melo, Betsaida; Guccione, Ernesto; Sebra, Robert; Shum, Elaine; Bakker, Jan; Kaufman, David A; Moreira, Andre L; Carossino, Mariano; Balasuriya, Udeni B R; Byun, Minji; Miraldi, Emily R; Albrecht, Randy A; Schotsaert, Michael; Garcia-Sastre, Adolfo; Chanda, Sumit K; Jeyasekharan, Anand D; TenOever, Benjamin R; Spivakov, Mikhail; Weirauch, Matthew T; Heinz, Sven; Chen, Honglin; Benner, Christopher; Richt, Juergen A; Marazzi, Ivan
The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of Top1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing Top1 inhibitors for COVID-19 in humans.
PMID: 33299999
ISSN: n/a
CID: 4843582