Sai‐Hong Ignatius Ou

University of California, Irvine

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Co-Authors

Alice T. Shaw

Massachusetts General Hospital

130

D. Ross Camidge

University of Colorado Denver

Viola W. Zhu

Harvard University

Pasi A. Jänne

Dana-Farber Cancer Institute

Shirish M. Gadgeel

Henry Ford Health System

Gregory J. Riely

Memorial Sloan Kettering Cancer Center

Misako Nagasaka

St. Marianna University School of Medicine

Siraj M. Ali

Superior University

James G. Christensen

Mirati Therapeutics (United States)

Melissa L. Johnson

Tennessee Oncology

Cooperative Institutions

Harvard University

208

Memorial Sloan Kettering Cancer Center

163

Dana-Farber Cancer Institute

154

Massachusetts General Hospital

151

The University of Texas MD Anderson Cancer Center

147

Pfizer (United States)

133

Samsung Medical Center

129

Emory University

103

Cornell University

101

University of California, Irvine

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Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)

Cancer Discovery (2017)

Alexander Drilon Salvatore Siena Sai‐Hong Ignatius Ou Manish R. Patel Myung‐Ju Ahn

Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 339.

ALK inhibitor

Trk receptor

10.1158/2159-8290.cd-16-1237

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Citations (724)

ERBB family fusions are recurrent and actionable oncogenic targets across cancer types

Frontiers in Oncology (2023)

Laura Schubert Andrew Elliott Anh T. Le Adriana Estrada‐Bernal Robert C. Doebele

Gene fusions involving receptor tyrosine kinases (RTKs) define an important class of genomic alterations with many successful targeted therapies now approved for ALK, ROS1, RET and NTRK gene fusions. Fusions involving the ERBB family of RTKs have been sporadically reported, but their frequency has not yet been comprehensively analyzed and functional characterization is lacking on many types of ERBB fusions. We analyzed tumor samples submitted to Caris Life Sciences (n=64,354), as well as the TCGA (n=10,967), MSK IMPACT (n=10,945) and AACR GENIE (n=96,324) databases for evidence of EGFR, ERBB2 and ERBB4 gene fusions. We also expressed several novel fusions in cancer cell lines and analyzed their response to EGFR and HER2 tyrosine kinase inhibitors (TKIs). In total, we identified 1,251 ERBB family fusions, representing an incidence of approximately 0.7% across all cancer types. EGFR, ERBB2, and ERBB4 fusions were most frequently found in glioblastoma, breast cancer and ovarian cancer, respectively. We modeled two novel types of EGFR and ERBB2 fusions, one with a tethered kinase domain and the other with a tethered adapter protein. Specifically, we expressed EGFR-ERBB4, EGFR-SHC1, ERBB2-GRB7 and ERBB2-SHC1, in cancer cell lines and demonstrated that they are oncogenic, regulate downstream signaling and are sensitive to small molecule inhibition with EGFR and HER2 TKIs. We found that ERBB fusions are recurrent mutations that occur across multiple cancer types. We also establish that adapter-tethered and kinase-tethered fusions are oncogenic and can be inhibited with EGFR or HER2 inhibitors. We further propose a nomenclature system to categorize these fusions into several functional classes.

ErbB

ERBB4

Protein kinase domain

Lapatinib

10.3389/fonc.2023.1115405

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Citations (8)

OA12.02 Updated Antitumor Activity of Crizotinib in Patients with MET Exon 14-Altered Advanced Non-Small Cell Lung Cancer

Journal of Thoracic Oncology (2018)

Alexander Drilon Jeffrey W. Clark Jared Weiss Sai‐Hong Ignatius Ou D. Ross Camidge

Adenosquamous carcinoma

10.1016/j.jtho.2018.08.300

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Citations (34)

Clinicopathologic Features of Non–Small-Cell Lung Cancer Harboring an NTRK Gene Fusion

JCO Precision Oncology (2018)

Anna F. Farago Martin S. Taylor Robert C. Doebele Viola W. Zhu Shivaani Kummar

Gene rearrangements involving NTRK1/2/3 can generate fusion oncoproteins containing the kinase domains of TRKA/B/C, respectively. These fusions are rare in non-small cell lung cancer (NSCLC), with frequency previously estimated to be <1%. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion-positive NSCLCs are not well characterized.We compiled a database of NSCLC cases harboring NTRK fusions. We characterized the clinical, molecular, and histologic features of these cases with central review of histology.We identified 11 NSCLC cases harboring NTRK gene fusions verified by next-generation sequencing (NGS) and with available clinical and pathologic data, forming the study cohort. Fusions involved NTRK1 (7 cases) and NTRK3 (4 cases), with 5 and 2 distinct fusion partners, respectively. Cohort patients were 55% male, with a median age at diagnosis of 47.6 years (range 25.3-86.0) and a median pack year history of 0 (range 0-58). 73% of patients had metastatic disease at diagnosis. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known oncogenic drivers were identified. Nine cases were adenocarcinoma, including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features; one was squamous cell carcinoma; and one was neuroendocrine carcinoma. By collating data on 4872 consecutively screened NSCLC cases from unique patients, we estimate a frequency of NTRK fusions in NSCLC of 0.23% (95% CI 0.11-0.40).NTRK fusions occur in NSCLCs across genders, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for NTRK fusions using a multiplexed NGS-based fusion assay.

Trk receptor

10.1200/po.18.00037

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Citations (166)

Enhancing the Atom Economy of Polyketide Biosynthetic Processes through Metabolic Engineering

Biotechnology Progress (2001)

Felipe Lombó Blaine A. Pfeifer Timothy Leaf Sai‐Hong Ignatius Ou Y. S. Kim

Polyketides, a large family of bioactive natural products, are synthesized from building blocks derived from α-carboxylated Coenzyme A thioesters such as malonyl-CoA and (2S)-methylmalonyl-CoA. The productivity of polyketide fermentation processes in natural and heterologous hosts is frequently limited by the availability of these precursors in vivo. We describe a metabolic engineering strategy to enhance both the yield and volumetric productivity of polyketide biosynthesis. The genes matB and matC from Rhizobium trifolii encode a malonyl-CoA synthetase and a putative dicarboxylate transport protein, respectively. These proteins can directly convert exogenous malonate and methylmalonate into their corresponding CoA thioesters with an ATP requirement of 2 mol per mol of acyl-CoA produced. Heterologous expression of matBC in a recombinant strain of Streptomyces coelicolor that produces the macrolactone 6-deoxyerythronolide B results in a 300% enhancement of macrolactone titers. The unusual efficiency of the bioconversion is illustrated by the fact that approximately one-third of the methylmalonate units added to the fermentation medium are converted into macrolactones. The direct conversion of inexpensive feedstocks such as malonate and methylmalonate into polyketides represents the most carbon- and energy-efficient route to these high value natural products and has implications for cost-effective fermentation of numerous commercial and development-stage small molecules.

Metabolic Engineering

Bioconversion

Actinorhodin

Heterologous

Heterologous expression

Malonate

10.1021/bp010045j

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Citations (50)

Supplementary Data from Circulating Cell-free DNA as a Prognostic Biomarker in Patients with Advanced ALK+ Non–small Cell Lung Cancer in the Global Phase III ALEX Trial

Rafał Dziadziuszko Solange Peters Tony Mok D. Ross Camidge Shirish M. Gadgeel

Supplementary Data from Circulating Cell-free DNA as a Prognostic Biomarker in Patients with Advanced ALK+ Non–small Cell Lung Cancer in the Global Phase III ALEX Trial

10.1158/1078-0432.22484174.v1

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Citations (0)

PD1-1-4: Low socio-economic status is an independent poor prognostic factor for survival in stage I non-small-cell lung cancer, and is independent of marital status, race, and surgical treatment. A population-based analysis of 19,702 stage I NSCLC patients in the California Cancer Registry

Journal of Thoracic Oncology (2007)

Sai‐Hong Ignatius Ou Jason A. Zell Argyrios Ziogas Hoda Anton‐Culver

Marital status

Univariate analysis

Performance status

10.1097/01.jto.0000283302.87195.17

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Citations (3)

Real-World Response and Outcomes in Patients With NSCLC With EGFR Exon 20 Insertion Mutations

JTO Clinical and Research Reports (2023)

Sai‐Hong Ignatius Ou Huamao Mark Lin Jin‐Liern Hong Yu Yin Shu Jin

This study describes treatment patterns and outcomes in patients with NSCLC with EGFR exon 20 insertions (EGFRex20ins) in the United States.The Flatiron Health electronic health record database was used to select three cohorts among patients diagnosed with NSCLC with EGFRex20ins (January 1, 2011-February 29, 2020): (1) first-line (1L) or patients receiving 1L therapy after documented EGFRex20ins; (2) second or later-line (≥2L) or patients receiving ≥2L therapy after documented EGFRex20ins; and (3) ≥2L postplatinum trial-aligned, or ≥2L patients previously treated with platinum chemotherapy whose baseline characteristics aligned with key eligibility criteria (initiating new treatment after documented EGFRex20ins and ≥1 previous treatment excluding mobocertinib or amivantamab) of the mobocertinib trial NCT02716116. Real-world end points were confirmed overall response rate, overall survival, and progression-free survival.Of 237 patients with EGFRex20ins-mutated NSCLC, 129 and 114 patients were included in the 1L and ≥2L cohorts, respectively. In 1L patients, platinum chemotherapy plus nonplatinum chemotherapy (31.0%) and EGFR tyrosine kinase inhibitors (28.7%) were the most common regimens. In ≥2L patients, immuno-oncology monotherapy (28.1%) and EGFR tyrosine kinase inhibitors (17.5%) were the most common index treatments. For any 1L, ≥2L, and ≥2L postplatinum trial-aligned patients, the confirmed overall response rate was 18.6%, 9.6%, and 14.0%, respectively; the median overall survival was 17.0, 13.6, and 11.5 months; the median progression-free survival was 5.2, 3.7, and 3.3 months, respectively.The outcomes for patients with NSCLC with EGFRex20ins were poor. This real-world study provides a benchmark on treatment outcomes in this patient population and highlights the unmet need for improved therapeutic options.

10.1016/j.jtocrr.2023.100558

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Citations (26)

A4-07: Prognostic factors for survival of stage I non-small cell lung cancer (NSCLC) patients: a population-based analysis of 19,702 stage I patients in the California Cancer Registry (CCR) from 1989 to 2003

Journal of Thoracic Oncology (2007)

Sai‐Hong Ignatius Ou Jason A. Zell Argyrios Ziogas Hoda Anton‐Culver

10.1097/01.jto.0000283117.52283.c6

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Citations (3)

Data from Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors

Garrett M. Frampton Siraj M. Ali Mark R. Rosenzweig Juliann Chmielecki Xinyuan Lu

<div>AbstractFocal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting.Significance: Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors. Cancer Discov; 5(8); 850–9. ©2015 AACR.See related commentary by Ma, p. 802.See related article by Paik et al., p. 842.This article is highlighted in the In This Issue feature, p. 783</div>

10.1158/2159-8290.c.6546132

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Citations (0)