Khan AJ, Vicini FA, Brown S, Haffty BG, Kearney T, Dale R, Lyden M, and Arthur D. (2013) Dosimetric Feasibility and Acute Toxicity in a Prospective Trial of Ultra-short Course Accelerated Partial Breast Irradiation (APBI) using a Multi-Lumen Balloon Brachytherapy Device. Ann Surg Oncol. 20(4):1295-301.
Dr. Khan’s Contribution to Science:
As a post-doctoral associate at Yale University School of Medicine, I worked on a translational project evaluating outcomes after breast conserving therapy in women with BRCA mutation-associated breast cancer. In this study, we collected specimens from women with breast cancer who were diagnosed at a young age and compared outcomes between women with wild-type disease and women with BRCA-mutant disease. We looked at endpoints of ipsilateral and contralateral breast cancer, as well as distant control and survival. I shared co-authorship when this seminal work was published in Lancet.
Haffty BG, Harrold E, Khan A, Pathare P, Ward BA, Matloff E, Alvarez-Franco M, Bale AE. (2002). Conservatively Managed Breast Cancer in Young Women: Outcome as a Function of BRCA 1/2 Status. Lancet, 27;359(9316),1471-7.
In a translational project that I led, and for which I personally performed experiments, we reported for the first time that treating irradiated cells with riluzole, a glutamate release inhibitor, increased cell death and DNA double strand breaks.
The publication was followed by three additional papers that continued to build on this work in different models, including a model of brain metastasis and gliomas. The United States Patent and Trademark Office (USPTO) awarded a patent for this use, and the drug is being developed for clinical use by Biohaven (trigriluzole, Biohaven New Haven CT); as a result, it may affect patient care in the near term.
A phase 1 trial of the drug in patients with melanoma brain metastases has activated at Dana Farber, with multiple participating institutions. As a result, my work has directly translated to a patient-centered clinical trial.
Khan AJ, Wall B, Ahlawat S, Green C, Schiff D, Mehnert JM, Goydos JS, Chen S, Haffty BG. Riluzole enhances ionizing radiation-induced cytotoxicity in human melanoma cells that ectopically express metabotropic glutamate receptor 1 in vitro and in vivo. Clin Cancer Res. 2011 Apr 1;17(7):1807-14. doi: 10.1158/1078-0432.CCR-10-1276. Epub 2011 Feb 15. PMID: 21325066; PMCID: PMC3070864.
Wall BA, Wangari-Talbot J, Shin SS, Schiff D, Sierra J, Yu LJ, Khan A, Haffty B, Goydos JS, Chen S. Disruption of GRM1-mediated signalling using riluzole results in DNA damage in melanoma cells. Pigment Cell Melanoma Res. 2014 Mar;27(2):263-74. doi: 10.1111/pcmr.12207. Epub 2014 Jan 22. PMID: 24330389; PMCID: PMC3947419
Wall BA, Yu LJ, Khan A, Haffty B, Goydos JS, Chen S. Riluzole is a radio-sensitizing agent in an in vivo model of brain metastasis derived from GRM1 expressing human melanoma cells. Pigment Cell Melanoma Res. 2015 Jan;28(1):105-9. doi: 10.1111/pcmr.12327. Epub 2014 Nov 28. PMID: 25363352; PMCID: PMC5661976.
Khan AJ, LaCava S, Mehta M, Schiff D, Thandoni A, Jhawar S, Danish S, Haffty BG, Chen S. The glutamate release inhibitor riluzole increases DNA damage and enhances cytotoxicity in human glioma cells, in vitro and in vivo. Oncotarget. 2019 Apr 19;10(29):2824-2834. doi: 10.18632/oncotarget.26854. PMID: 31073373; PMCID: PMC6497458.
Level I evidence supports the use of shorter, or hypofractionated, breast radiotherapy schedules in diverse cohorts of people with breast cancer. However, the implications of these shorter schedules when adopted on a national scale were unknown. We investigated wide-scale adoption of shorter radiotherapy schedules in a Markov model and demonstrated that adoption of these shorter schedules in countries with limited radiotherapy resources can actually improve breast cancer-survival and other endpoints by improving access to therapy when a backlog of demand exists.
Relatedly, I have been the Principal Investigator (PI) of three investigator-initiated trials examining shorter novel courses of breast radiotherapy, two of which were multi-institutional. The most significant of these was recently reported and serves as the basis for a national randomized trial of hypofractionated postmatectomy radiation therapy (PMRT) vs conventional PMRT (Alliance 221505), for which I am one of the PIs.
Khan AJ, Rafique R, Zafar W, Shah C, Haffty BG, Vicini F, Jamshed A, Zhao Y. Nation-Scale Adoption of Shorter Breast Radiation Therapy Schedules Can Increase Survival in Resource Constrained Economies: Results From a Markov Chain Analysis. Int J Radiat Oncol Biol Phys. 2017 Feb 1;97(2):287-295. doi: 10.1016/j.ijrobp.2016.10.002. Epub 2016 Oct 11. PMID: 27986343.
Khan AJ, Poppe MM, Goyal S, Kokeny KE, Kearney T, Kirstein L, Toppmeyer D, Moore DF, Chen C, Gaffney DK, Haffty BG. Hypofractionated Postmastectomy Radiation Therapy Is Safe and Effective: First Results From a Prospective Phase II Trial. J Clin Oncol. 2017 Jun 20;35(18):2037-2043. doi: 10.1200/JCO.2016.70.7158. Epub 2017 May 1. PMID: 28459606; PMCID: PMC5476174.
Khan AJ, Chen PY, Yashar C, Poppe MM, Li L, Abou Yehia Z, Vicini FA, Moore D, Dale R, Arthur D, Shah C, Haffty BG, Kuske R. Three-Fraction Accelerated Partial Breast Irradiation (APBI) Delivered With Brachytherapy Applicators Is Feasible and Safe: First Results From the TRIUMPH-T Trial. Int J Radiat Oncol Biol Phys. 2019 May 1;104(1):67-74. doi: 10.1016/j.ijrobp.2018.12.050. Epub 2019 Jan 4. PMID: 30611839; PMCID: PMC7373303.
There are now a several agents that can inhibit DNA damage repair. However, the rationale for therapeutic ratio (tumor cells to normal cells) is stronger for some of these agents than for others. Specifically for DNA-protein kinase (PK) inhibition, a major regulator of non-homologous end joining, the rationale is not clear. We attempted to demonstrate therapeutic ratio and to begin understanding the basis for it.
Khan AJ, Misenko SM, Thandoni A, Schiff D, Jhawar SR, Bunting SF, Haffty BG. VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells. Oncotarget. 2018 May 25;9(40):25833-25841. doi: 10.18632/oncotarget.25383. PMID: 29899825; PMCID: PMC5995231.
