MD, New York University
At a Glance
- The Lok lab focuses on novel therapeutic development and mechanisms of resistance in lung cancer.
- We have a particular interest in mechanisms and therapeutics related to DNA repair and radiation medicine.
- We employ functional genomic and molecular biology approaches with additional expertise in genome-wide CRISPR screening and high-throughput drug library screens.
- The lab has a growing “living biobank” of small cell lung cancer patient-derived xenograft models developed from the circulating-tumor-cells extracted from peripheral blood draws.
- We translate our findings directly into patient care through the development of clinical trials.
Dr. Benjamin Lok is a Clinician-Scientist at the Princess Margaret Cancer Centre and Assistant Professor of Radiation Oncology and Medical Biophysics at the University of Toronto. Dr. Lok serves as Staff Radiation Oncologist – Clinician Scientist in the Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network. He is also an Associate Member in the Institute of Medical Science at the University of Toronto.
Dr. Lok obtained his MD in 2012 from New York University, followed by internship at the New York University Langone Medical Center. He subsequently completed his Radiation Oncology residency training at Memorial Sloan Kettering Cancer Center, where Dr. Lok also served as the Chief Resident during his final year. Dr. Lok has received extensive training in laboratory research; initially mentored by Dr. Simon Powell on DNA damage and repair response. Dr. Lok then conducted postdoctoral work in Dr. Charles Rudin’s lab where he investigated the role of PARP inhibitors (Lok et al Clin Cancer Res 2016) and an epigenetic resistance mechanism in small cell lung cancer (Gardner, Lok et al Cancer Cell 2017). Since establishing his independent laboratory at the Princess Margaret Cancer Centre in 2017, Dr. Lok has published work investigating the novel combination of PARP inhibitors with radiotherapy for SCLC (Laird*, Lok* et al Clin Cancer Res 2018), which has led to the development of two investigator-initiated clinical trials examining this combination where he serves as lead PI or collaborating investigator on the respective trials. Dr. Lok has conducted work examining the utility of a novel [F18]PARPi PET radiotracer in assessing PARP inhibitor drug target engagement in SCLC animal models with significant translational implications (Laird*, Lok* et al J Thorac Oncol 2019; Carney et al Nat Commun 2018). Dr. Lok's clinical and research focus is directed towards improving outcomes for lung cancer patients by understanding mechanisms of resistance and developing novel therapeutic strategies.
The mission of Dr. Lok's laboratory is to improve the outcomes of lung cancer patients by understanding the mechanisms of therapeutic resistance and identifying novel therapeutic targets, particularly those related to DNA repair.
Understanding the predictive biomarker SLFN11 in small cell lung cancer (SCLC)
SCLC is a deadly disease that is initially sensitive to various DNA damaging therapies. Current therapy relies on two broadly used chemotherapeutic agents, cisplatin and etoposide. Identifying predictive biomarkers of response will allow for improved risk stratification and direct personalized therapy for these patients.
One biomarker that predicts for drug response to various DNA damaging therapies - including cisplatin, etoposide and PARP inhibitors - in SCLC is expression of a gene, SLFN11. However, little is known about how SLFN11 mediates therapeutic sensitivity. My laboratory is interested in understanding the mechanism of how SLFN11 sensitizes SCLC to these widely used therapies. By deepening our understanding of this novel biomarker, we will be able to develop future therapies that exploit these discoveries.
Epigenetic targeted therapies for SCLC
Recurrent targetable oncogenic driver mutations are rare in SCLC, instead a hallmark of this disease is loss of two well-known tumor suppressors, TP53 and RB1. Though pharmacologically targeting these pathways is currently difficult, a recent advance in understanding epigenetics and how it applies to SCLC has provided us a way forward in applying targeted therapeutics. We have shown that the dependency of SCLC on EZH2 activity (a methyltransferase that functions on H3K27 and adds a tri-methyl suppressive chromatin mark) leads to chemotherapeutic resistance that can be reversed with inhibitors against EZH2. Remarkably, impressive synergy of EZH2 inhibition with chemotherapy has led to durable responses in preclinical models. Further discovery of epigenetic pathways that are targetable and improve outcomes in SCLC could dramatically change the current treatment paradigm. We are leveraging the expertise and resources available at the Structural Genomics Consortium to screen a library of epigenetic chemical probes to identify novel therapeutic approaches for SCLC.
Improving translational drug development with circulating-tumor-cell patient-derived xenograft (CDX) models
PDX models have been shown to more closely reflect the biology of their tumors of origin than cell line xenografts. Novel therapeutic testing in PDXs can also more accurately reflect the subsequent experience in human patients. However, PDX generation typically involves surgically resected specimens or core biopsies of sufficient tissue quality – both approaches can be difficult and unnecessary in SCLC patients.
A recent advance to overcome these barriers is the derivation of PDX models from circulating-tumor-cells (CTC) obtained from peripheral blood – known as CDX model. This innovation broadens the patient population who may be able to benefit from personalized xenograft models and allow for larger numbers of diverse tumor models for cancer research. We have established this expertise at our institute to increase availability of translationally relevant xenograft models to improve drug development and success in future clinical trials.
- Laird J*, Lok BH*, Carney B, Kossatz S, de Stanchina E, Reiner T, Poirier JT, Rudin CM. Positron-Emission Tomographic Imaging of a Fluorine 18-Radiolabeled Poly(ADP-Ribose) Polymerase 1 Inhibitor Monitors the Therapeutic Efficacy of Talazoparib in SCLC Patient-Derived Xenografts. J Thorac Oncol. 2019 Jun 10. pii: S1556-0864(19)30453-8. doi: 10.1016/j.jtho.2019.05.032. [Epub ahead of print] [(*) indicates co-first authorship]
- Laird JH*, Lok BH*, Ma J, Bell A, de Stanchina E, Poirier JT, Rudin CM. Talazoparib is a Potent Radiosensitizer in Small Cell Lung Cancer Cell Lines and Xenografts. Clin Cancer Res. 2018 Oct 15;24(20):5143-5152. doi: 10.1158/1078-0432.CCR-18-0401. Epub 2018 Jun 26. [(*) indicates co-first authorship]
- Sabari JK*, Lok BH*, Laird JH, Poirier JT, Rudin CM. Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol. 2017 Sep;14(9):549-561. Epub 2017 May 23. Review. [(*) indicates co-first authorship]
- Gardner EE, Lok BH, Schneeberger VE, Miles LA, Arnold PK, Desmeules P, Ni A, Khodos I, de Stanchina E, Rekhtman N, Dowlati A, Massion PP, Poirier JT, Rudin CM. “Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis.” Cancer Cell. 2017 Feb 13;31(2):286-299.
- Lok BH, Gardner EE, Schneeberger VE, Ni A, Desmeules P, Rekhtman N, de Stanchina E, Teicher BA, Riaz R, Powell SN, Poirier JT, Rudin CM. “PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer.” Clin Cancer Res. 2017 Jan 15; 23(2):523-535. Epub 2016 Jul 20.
- Lok BH, Carley AC, Tchang B, Powell SN. “Rad52 inactivation is synthetically lethal with deficiencies in the BRCA1-PALB2 pathway of homologous recombination in addition to BRCA2.” Oncogene. 2013 Jul 25;32(30):3552-8.
- Lok BH, Powell SN. “Molecular Pathways: Understanding the Role of Rad52 in Homologous Recombination for Therapeutic Advancement.” Clin Cancer Res. 2012 Dec 1;18(23):6400-6.