Mustafa Khasraw

Overview:

I am a medical oncologist, neuro-oncologist, tenured professor of medicine and neurooncology, and Deputy Director of the Center for Cancer Immunotherapy, Duke Cancer Institute, where are tasked to speed up clinical research and translation for scientists across all departments and all tumor types at Duke, who have made discoveries that show promise for developing new immunotherapies.

I am leading several clinical and translational programs with significant laboratory collaborations with an interest in innovative trials designed to improve the outcome of patients with cancers of the CNS. In addition, I am the principal investigator on first in human phase I immunotherapy clinical trials in solid tumors. 

I serve as an advisor and grant reviewer for several non-profits and patient advocacy groups. I am a Fellow of the Royal Australasian College of Physicians and an Elected Fellow of the Royal College of Physicians (UK). 

Positions:

Professor of Neurosurgery

Neurosurgery
School of Medicine

Professor in Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2001

Rijksuniversiteit Groningen (The Netherlands)

Grants:

Astellas 1951-CL-0101

Administered By
Duke Cancer Institute
Awarded By
Astellas Pharma Global Development, Inc
Role
Principal Investigator
Start Date
End Date

Celldex CDX-527

Administered By
Duke Cancer Institute
Awarded By
Celldex Therapeutics, Inc.
Role
Principal Investigator
Start Date
End Date

Publications:

Leveraging external data in the design and analysis of clinical trials in neuro-oncology.

Integration of external control data, with patient-level information, in clinical trials has the potential to accelerate the development of new treatments in neuro-oncology by contextualising single-arm studies and improving decision making (eg, early stopping decisions). Based on a series of presentations at the 2020 Clinical Trials Think Tank hosted by the Society of Neuro-Oncology, we provide an overview on the use of external control data representative of the standard of care in the design and analysis of clinical trials. High-quality patient-level records, rigorous methods, and validation analyses are necessary to effectively leverage external data. We review study designs, statistical methods, risks, and potential distortions in using external data from completed trials and real-world data, as well as data sources, data sharing models, ongoing work, and applications in glioblastoma.
Authors
Rahman, R; Ventz, S; McDunn, J; Louv, B; Reyes-Rivera, I; Polley, M-YC; Merchant, F; Abrey, LE; Allen, JE; Aguilar, LK; Aguilar-Cordova, E; Arons, D; Tanner, K; Bagley, S; Khasraw, M; Cloughesy, T; Wen, PY; Alexander, BM; Trippa, L
MLA Citation
Rahman, Rifaquat, et al. “Leveraging external data in the design and analysis of clinical trials in neuro-oncology.Lancet Oncol, vol. 22, no. 10, Oct. 2021, pp. e456–65. Pubmed, doi:10.1016/S1470-2045(21)00488-5.
URI
https://scholars.duke.edu/individual/pub1498359
PMID
34592195
Source
pubmed
Published In
Lancet Oncol
Volume
22
Published Date
Start Page
e456
End Page
e465
DOI
10.1016/S1470-2045(21)00488-5

A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.

PURPOSE: To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2'-deoxyguanosine (THIO) in gliomas both in vitro and in vivo. EXPERIMENTAL DESIGN: A panel of human and mouse glioma cell lines was used to test therapeutic efficacy of THIO using cell viability assays, flow cytometric analyses, and immunofluorescence. Integrated analyses of RNA sequencing and reverse-phase protein array data revealed the potential antitumor mechanisms of THIO. Four patient-derived xenografts (PDX), two patient-derived organoids (PDO), and two xenografts of human glioma cell lines were used to further investigate the therapeutic efficacy of THIO. RESULTS: THIO was effective in the majority of human and mouse glioma cell lines with no obvious toxicity against normal astrocytes. THIO as a monotherapy demonstrated efficacy in three glioma cell lines that had acquired resistance to temozolomide. In addition, THIO showed efficacy in four human glioma cell lines grown as neurospheres by inducing apoptotic cell death. Mechanistically, THIO induced telomeric DNA damage not only in glioma cell lines but also in PDX tumor specimens. Integrated computational analyses of transcriptomic and proteomic data indicated that THIO significantly inhibited cell invasion, stem cell, and proliferation pathways while triggering DNA damage and apoptosis. Importantly, THIO significantly decreased tumor proliferation in two PDO models and reduced the tumor size of a glioblastoma xenograft and a PDX model. CONCLUSIONS: The current study established the therapeutic role of THIO in primary and recurrent gliomas and revealed the acute induction of telomeric DNA damage as a primary antitumor mechanism of THIO in gliomas.
Authors
Yu, S; Wei, S; Savani, M; Lin, X; Du, K; Mender, I; Siteni, S; Vasilopoulos, T; Reitman, ZJ; Ku, Y; Wu, D; Liu, H; Tian, M; Chen, Y; Labrie, M; Charbonneau, CM; Sugarman, E; Bowie, M; Hariharan, S; Waitkus, M; Jiang, W; McLendon, RE; Pan, E; Khasraw, M; Walsh, KM; Lu, Y; Herlyn, M; Mills, G; Herbig, U; Wei, Z; Keir, ST; Flaherty, K; Liu, L; Wu, K; Shay, JW; Abdullah, K; Zhang, G; Ashley, DM
MLA Citation
Yu, Shengnan, et al. “A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.Clin Cancer Res, Sept. 2021. Pubmed, doi:10.1158/1078-0432.CCR-21-0374.
URI
https://scholars.duke.edu/individual/pub1497999
PMID
34593527
Source
pubmed
Published In
Clinical Cancer Research
Published Date
DOI
10.1158/1078-0432.CCR-21-0374

Bintrafusp alfa (M7824), a bifunctional fusion protein targeting TGF-β and PD-L1: results from a phase I expansion cohort in patients with recurrent glioblastoma.

Background: For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 antibody blocking PD-L1. Methods: In this phase I, open-label expansion cohort (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety. Results: As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5-20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non-complete response/non-progressive disease. Median progression-free survival (PFS) was 1.4 (95% confidence interval [CI], 1.2-1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6-9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3-95.7%) for patients with IDH-mutant GBM (n = 6) and 13.8% (3.9-31.7%) for patients with IDH-wild-type GBM (n = 29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [n = 6]). Conclusions: The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.
Authors
Khasraw, M; Weller, M; Lorente, D; Kolibaba, K; Lee, CK; Gedye, C; I de La Fuente, M; Vicente, D; Reardon, DA; Gan, HK; Scott, AM; Dussault, I; Helwig, C; Ojalvo, LS; Gourmelon, C; Groves, M
MLA Citation
Khasraw, Mustafa, et al. “Bintrafusp alfa (M7824), a bifunctional fusion protein targeting TGF-β and PD-L1: results from a phase I expansion cohort in patients with recurrent glioblastoma.Neurooncol Adv, vol. 3, no. 1, Jan. 2021, p. vdab058. Pubmed, doi:10.1093/noajnl/vdab058.
URI
https://scholars.duke.edu/individual/pub1484842
PMID
34056607
Source
pubmed
Published In
Neuro Oncology Advances
Volume
3
Published Date
Start Page
vdab058
DOI
10.1093/noajnl/vdab058

Designing Clinical Trials for Combination Immunotherapy: A Framework for Glioblastoma.

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.
Authors
Singh, K; Batich, KA; Wen, PY; Tan, AC; Bagley, SJ; Lim, M; Platten, M; Colman, H; Ashley, DM; Chang, SM; Rahman, R; Galanis, E; Mansouri, A; Puduvalli, VK; Reardon, DA; Sahebjam, S; Sampson, JH; Simes, J; Berry, DA; Zadeh, G; Cloughesy, TF; Mehta, MP; Piantadosi, S; Weller, M; Heimberger, AB; Khasraw, M
MLA Citation
Singh, Kirit, et al. “Designing Clinical Trials for Combination Immunotherapy: A Framework for Glioblastoma.Clin Cancer Res, Sept. 2021. Pubmed, doi:10.1158/1078-0432.CCR-21-2681.
URI
https://scholars.duke.edu/individual/pub1497055
PMID
34561270
Source
pubmed
Published In
Clinical Cancer Research
Published Date
DOI
10.1158/1078-0432.CCR-21-2681

Targeting Immunometabolism in Glioblastoma.

We have only recently begun to understand how cancer metabolism affects antitumor responses and immunotherapy outcomes. Certain immunometabolic targets have been actively pursued in other tumor types, however, glioblastoma research has been slow to exploit the therapeutic vulnerabilities of immunometabolism. In this review, we highlight the pathways that are most relevant to glioblastoma and focus on how these immunometabolic pathways influence tumor growth and immune suppression. We discuss hypoxia, glycolysis, tryptophan metabolism, arginine metabolism, 2-Hydroxyglutarate (2HG) metabolism, adenosine metabolism, and altered phospholipid metabolism, in order to provide an analysis and overview of the field of glioblastoma immunometabolism.
Authors
Mohan, AA; Tomaszewski, WH; Haskell-Mendoza, AP; Hotchkiss, KM; Singh, K; Reedy, JL; Fecci, PE; Sampson, JH; Khasraw, M
MLA Citation
Mohan, Aditya A., et al. “Targeting Immunometabolism in Glioblastoma.Front Oncol, vol. 11, 2021, p. 696402. Pubmed, doi:10.3389/fonc.2021.696402.
URI
https://scholars.duke.edu/individual/pub1488057
PMID
34222022
Source
pubmed
Published In
Frontiers in Oncology
Volume
11
Published Date
Start Page
696402
DOI
10.3389/fonc.2021.696402

Research Areas:

Anti-cancer
Cancer
Cancer Therapy Resistance
Cancer Vaccines
Cancer genes
Cancer--Immunotherapy
Immunotherapy