David Ashley

Overview:

Dr. Ashley's primary research focus is laboratory based, investigating the role of immunotherapy as a novel approach to the treatment of tumors of the central nervous system (CNS). Since beginning his appointment at the faculty level at Duke in August of 1995 his activities have centered on two main areas of investigation. The first involves both in vivo and in vitro studies of the use of molecular therapeutics to target a CNS tumor associated antigen. The second area of interest comprises a detailed analysis of the role of TGF beta, a protein messenger produced by tumors of the CNS, both in the pathogenesis of disease and as a possible target for immunotherapy.

In addition to his laboratory role Dr. Ashley is involved in the design and application of a variety of clinical research protocols in the treatment of children with malignant brain tumors.

Positions:

Rory David Deutsch Distinguished Professor of Neuro-Oncology

Neurosurgery
School of Medicine

Professor of Neurosurgery

Neurosurgery
School of Medicine

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Professor in Pathology

Pathology
School of Medicine

Professor in Pediatrics

Pediatrics, Hematology-Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

F.R.A.C.P. 1993

Royal Australasian College of Physicians (Australia)

M.B.B.S. 1994

University of Melbourne (Australia)

Ph.D. 1998

University of Melbourne (Australia)

Grants:

LGG-14C03: A Phase III study comparing two carboplatin containing regimens for children and young adults with previously untreated low grade glioma

Administered By
Duke Cancer Institute
Awarded By
Ann & Robert H Lurie Children's Hospital of Chicago
Role
Principal Investigator
Start Date
End Date

SJMB12: A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma

Administered By
Pediatrics, Hematology-Oncology
Awarded By
St. Jude Children's Research Hospital
Role
Principal Investigator
Start Date
End Date

NEWLY DIAGNOSED CHILDREN (LESS THAN 10 YEARS OLD) WITH MEDULLOBLASTOMA AND OTHER CENTRAL NERVOUS SYSTEMPRIMITIVE NEURO-ECTODERMAL TUMORS:CLINICAL AND MOLECULAR RISK-TAILORED INTENSIVE AND COMPRESSED INDUCTION CHEMOTHERAPY FOLLOWED BY CONSOLIDATION WI

Administered By
Duke Cancer Institute
Awarded By
Research Institute at Nationwide Children's Hospital
Role
Principal Investigator
Start Date
End Date

Collaborative Network for Neuroooncology Clinical Trials (CONNECT)

Administered By
Duke Cancer Institute
Awarded By
Cincinnati Children's Hospital Medical Center
Role
Principal Investigator
Start Date
End Date

A Phase II study of Panobinostat in Paediatric, Adolescent and Young Adult Patients with Solid Tumours (ATRT)

Administered By
Duke Cancer Institute
Awarded By
Australian and New Zealand Children's Haematology/Oncology Group
Role
Principal Investigator
Start Date
End Date

Publications:

Atypical Teratoid Rhabdoid Tumours Are Susceptible to Panobinostat-Mediated Differentiation Therapy.

Atypical teratoid rhabdoid tumour (ATRT) is a rare but highly aggressive undifferentiated solid tumour arising in the central nervous system and predominantly affecting infants and young children. ATRT is exclusively characterized by the inactivation of SMARCB1, a member of the SWI/SNF chromatin remodelling complex that is essential for the regulation of large sets of genes required for normal development and differentiation. Histone deacetylase inhibitors (HDACi) are a promising anticancer therapy and are able to mimic the normal acetylation functions of SMARCB1 in SMARCB1-deficient cells and drive multilineage differentiation in extracranial rhabdoid tumours. However, the potential efficacy of HDACi in ATRT is unknown. Here, we show that human ATRT cells are highly responsive to the HDACi panobinostat and that sustained treatment leads to growth arrest, increased cell senescence, decreased clonogenicity and induction of a neurogenesis gene-expression profile. Furthermore, in an orthotopic ATRT xenograft model, continuous panobinostat treatment inhibits tumour growth, increases survival and drives neuronal differentiation as shown by the expression of the neuronal marker, TUJ1. Collectively, this preclinical study supports the therapeutic potential of panobinostat-mediated differentiation therapy for ATRT.
Authors
Chong, WC; Jayasekara, WSN; Vaghjiani, VG; Parackal, S; Sun, C; Popovski, D; Algar, EM; Firestein, R; Wood, PJ; Khan, S; Huang, A; Ashley, DM; Downie, P; Cain, JE
MLA Citation
Chong, Wai C., et al. “Atypical Teratoid Rhabdoid Tumours Are Susceptible to Panobinostat-Mediated Differentiation Therapy.Cancers (Basel), vol. 13, no. 20, Oct. 2021. Pubmed, doi:10.3390/cancers13205145.
URI
https://scholars.duke.edu/individual/pub1499392
PMID
34680294
Source
pubmed
Published In
Cancers
Volume
13
Published Date
DOI
10.3390/cancers13205145

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

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

Primary brain tumor patients admitted to a US intensive care unit: a descriptive analysis.

Purpose: To describe our population of primary brain tumor (PBT) patients, a subgroup of cancer patients whose intensive care unit (ICU) outcomes are understudied. Methods: Retrospective analysis of PBT patients admitted to an ICU between 2013 to 2018 for an unplanned need. Using descriptive analyses, we characterized our population and their outcomes. Results: Fifty-nine PBT patients were analyzed. ICU mortality was 19% (11/59). The most common indication for admission was seizures (n = 16, 27%). Conclusion: Our ICU mortality of PBT patients was comparable to other solid tumor patients and the general ICU population and better than patients with hematological malignancies. Further study of a larger population would inform guidelines for triaging PBT patients who would most benefit from ICU-level care.
Authors
Kang, JH; Swisher, CB; Buckley, ED; Herndon, JE; Lipp, ES; Kirkpatrick, JP; Desjardins, A; Friedman, HS; Johnson, MO; Randazzo, DM; Ashley, DM; Peters, KB
MLA Citation
Kang, Jennifer H., et al. “Primary brain tumor patients admitted to a US intensive care unit: a descriptive analysis.Cns Oncol, vol. 10, no. 3, Sept. 2021, p. CNS77. Pubmed, doi:10.2217/cns-2021-0009.
URI
https://scholars.duke.edu/individual/pub1497219
PMID
34545753
Source
pubmed
Published In
Cns Oncology
Volume
10
Published Date
Start Page
CNS77
DOI
10.2217/cns-2021-0009

Systematic review of combinations of targeted or immunotherapy in advanced solid tumors.

With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.
Authors
Tan, AC; Bagley, SJ; Wen, PY; Lim, M; Platten, M; Colman, H; Ashley, DM; Wick, W; Chang, SM; Galanis, E; Mansouri, A; Khagi, S; Mehta, MP; Heimberger, AB; Puduvalli, VK; Reardon, DA; Sahebjam, S; Simes, J; Antonia, SJ; Berry, D; Khasraw, M
MLA Citation
Tan, Aaron C., et al. “Systematic review of combinations of targeted or immunotherapy in advanced solid tumors.J Immunother Cancer, vol. 9, no. 7, July 2021. Pubmed, doi:10.1136/jitc-2021-002459.
URI
https://scholars.duke.edu/individual/pub1488074
PMID
34215688
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
9
Published Date
DOI
10.1136/jitc-2021-002459