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:

BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS

<jats:title>Abstract</jats:title> <jats:p>Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes. While it is well established that Myc functions by binding to its target genes to regulate their transcription, the distribution of the transcriptional output across human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructures, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly in genes of involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc’s expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on the aforementioned infrastructure genes, which was accompanied by the abrogation of MB cell’s proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, gain new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in MB cells empowered by a high level of Myc oncoprotein.</jats:p>
Authors
Yang, R; Wang, W; Dong, M; Roso, K; Bao, X; Pirozzi, C; Bigner, D; Yan, H; Ashley, D; Zhabotynsky, V; Zou, F; He, Y
MLA Citation
Yang, Rui, et al. “BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS.” Neuro Oncology, vol. 23, no. Supplement_1, Oxford University Press (OUP), 2021, pp. i5–i5. Crossref, doi:10.1093/neuonc/noab090.017.
URI
https://scholars.duke.edu/individual/pub1489697
Source
crossref
Published In
Neuro Oncology
Volume
23
Published Date
Start Page
i5
End Page
i5
DOI
10.1093/neuonc/noab090.017

EPCT-01. A NOVEL PEPTIDE VACCINE DIRECTED TO CMV PP65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Introduction</jats:title> <jats:p>The cytomegalovirus (CMV) antigen, pp65, is ubiquitously expressed in malignant glioma and medulloblastoma but not in healthy brain. The objective of this Phase I trial (NCT03299309) was to assess the safety and feasibility of a novel pp65 peptide vaccine (PEP-CMV) in children and young adults with recurrent medulloblastoma and malignant glioma.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Vaccines contain a synthetic long peptide (SLP) of 26 amino acids encoding multiple potential class I, class II, and antibody epitopes of CMV pp65 across several haplotypes. This SLP is administered as an emulsion in Montanide ISA 51. Patients receive a single course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning, then vaccines administered intradermally every two weeks for 3 doses, then monthly.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>To date, 22 patients have been enrolled. Diagnoses include medulloblastoma (n=2), glioblastoma (n=12), anaplastic oligodendroglioma (n=2), anaplastic astrocytoma (n=3), and malignant glioma NOS (n=3). Mean number of prior treatment regimens is 4.9 (range 1–12). Mean age is 22yo (range 6–35) and 45% of patients are male. The median KPS is 80. The median number of vaccines given at time of analysis is 3.3 (range 1–12). There have been no ≥ 3 Grade toxicities related to the vaccine. One patient developed nausea, vomiting, palpitations, and tachycardia after vaccination and had elevated inflammatory cytokines consistent with cytokine release syndrome. Median PFS is 2.5 months (95% CI: 1.7,4.5) and median OS is 6.5 months (95% CI 3.3, 7.9). Immune response to pp65 as determined by ELISpot was found in 75% of patients. On MRI 6 of the 11 evaluable patients have had at least stable disease with three of those having a partial response.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Preliminary results demonstrate that PEP-CMV is well-tolerated and elicits an immune response in heavily pretreated, multiply recurrent patients. A multi-institutional Phase II trial is scheduled to open fall 2021.</jats:p> </jats:sec>
Authors
Thompson, E; Landi, D; Archer, G; Lipp, E; Walter, A; Archambault, B; Balajonda, B; Flahiff, C; Jaggers, D; Herndon, J; Buckley, E; Schroeder, K; Randazzo, D; Desjardins, A; Johnson, M; Peters, K; Khasraw, M; Malinzak, M; Michell, D; Ashley, D; Sampson, J
MLA Citation
Thompson, Eric, et al. “EPCT-01. A NOVEL PEPTIDE VACCINE DIRECTED TO CMV PP65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL.” Neuro Oncology, vol. 23, no. Supplement_1, Oxford University Press (OUP), 2021, pp. i46–i46. Crossref, doi:10.1093/neuonc/noab090.187.
URI
https://scholars.duke.edu/individual/pub1489722
Source
crossref
Published In
Neuro Oncology
Volume
23
Published Date
Start Page
i46
End Page
i46
DOI
10.1093/neuonc/noab090.187

LGG-08. TREATMENT OUTCOMES AND TOLERABILITY OF TRAMETINIB IN PROGRESSIVE CIRCUMSCRIBED LOW-GRADE GLIOMAS

<jats:title>Abstract</jats:title> <jats:p>Circumscribed low-grade gliomas comprise roughly one-third of pediatric CNS tumors. Most of these tumors are caused by activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Drugs targeting the MAPK pathway are effective in other cancers and are being utilized in low-grade gliomas. We describe treatment outcomes and toxicities in a series of thirteen low-grade glioma patients treated with trametinib. We performed a retrospective chart review to evaluate response on T2/FLAIR MRI images per updated RANO criteria, visual outcomes, tolerability, and durability of response in progressive low-grade glioma patients treated with trametinib. Thirteen patients age 22 months to 34 years were included. Best radiographic response on therapy included 2/13 partial response, 3/13 minimal response, 5/13 stable disease, and 3/13 progressive disease. Diagnoses included pilocytic astrocytoma (n=6), desmoplastic infantile ganglioglioma (DIG; n=1), and low-grade glial neoplasms (n=2). Molecular drivers included BRAF:KIAA1549 fusion (n=3), V600E mutation (n=1), and somatic NF1 mutation (n=1). Three patients had germline NF1. In patients with partial or minimal response, best response was seen after longer durations of therapy; 4 of 5 best responses occurred after at least 12 months on therapy. Five patients completed prescribed therapy. Three patients remain stable off therapy at 6, 12, and 21 months; two patients recurred at 1 and 10 months off therapy. Skin manifestations were the predominant form of toxicity. This was more severe in older males, and symptoms improved with intermittent dosing. All patients with optic pathway tumors showed at least stable vision throughout treatment, with some patients having dramatic improvement. Trametinib is effective and well-tolerated in patients with low-grade glioma. Dermatologic toxicity can be mitigated by intermittent dosing. Best responses tended to occur later in therapy, sometimes after relatively stable MRIs. Patients with optic pathway lesions showed stable to improved vision even in the absence of significant radiographic response.</jats:p>
Authors
Hanzlik, E; Archambault, B; Dairi, M; Schroeder, K; Patel, M; Lipp, ES; Boucree, S; Peters, K; Ashley, D; Landi, D
MLA Citation
Hanzlik, Emily, et al. “LGG-08. TREATMENT OUTCOMES AND TOLERABILITY OF TRAMETINIB IN PROGRESSIVE CIRCUMSCRIBED LOW-GRADE GLIOMAS.” Neuro Oncology, vol. 23, no. Supplement_1, Oxford University Press (OUP), 2021, pp. i32–33. Crossref, doi:10.1093/neuonc/noab090.132.
URI
https://scholars.duke.edu/individual/pub1489822
Source
crossref
Published In
Neuro Oncology
Volume
23
Published Date
Start Page
i32
End Page
i33
DOI
10.1093/neuonc/noab090.132

Spiritual well-being and its association with health-related quality of life in primary brain tumor patients.

Background: Spirituality can impact patients' attitudes and decisions about treatment and end-of-life care when coping with cancer. Previous studies documented health-related quality of life (HRQoL) and spiritual well-being (SWB) as positively correlated within a general cancer patient population, but little is known about their association in the primary brain tumor population. We sought to measure SWB in primary brain tumor patients and evaluate whether it was associated with HRQoL. Methods: Six-hundred and six patients treated at The Preston Robert Tisch Brain Tumor Center at Duke between December 16, 2013 and February 28, 2014 with data in the PRoGREss registry are included in this retrospective analysis. Each patient completed the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being 12 (FACIT-Sp-12) and -Fatigue (FACIT-F), and the Functional Assessment of Cancer Therapy-General and -Brain (FACT-G and FACT-Br). Results: Mean age was 49.1 years (SD = 13.5 years), male (N = 328, 54.1%), married (N = 404, 66.7%), at least college-educated (N = 381, 62.9%), and diagnosed with a high-grade glioma (N = 412, 68.0%). Multiple regression analyses were performed on both the FACT-G and the FACT-Br using the FACIT-Sp-12 sub-scales of Meaning/Peace and Faith, FACIT-F, belief in God or a higher power, prayer, gender, tumor grade, and Karnofsky Performance Status (KPS) as predictors. We found that greater SWB (measured by FACIT-Sp-12) was associated with better HRQoL (measured by FACT-G and FACT-Br; p < .0001). Conclusion: The association between reported SWB and reported improved HRQoL emphasizes the importance of spirituality in primary brain tumor patients, suggesting SWB must be considered in strategies to improve HRQoL.
Authors
Randazzo, DM; McSherry, F; Herndon, JE; Affronti, ML; Lipp, ES; Miller, ES; Woodring, S; Healy, P; Jackman, J; Crouch, B; Desjardins, A; Ashley, DM; Friedman, HS; Peters, KB
MLA Citation
Randazzo, Dina M., et al. “Spiritual well-being and its association with health-related quality of life in primary brain tumor patients.Neurooncol Pract, vol. 8, no. 3, June 2021, pp. 299–309. Pubmed, doi:10.1093/nop/npaa084.
URI
https://scholars.duke.edu/individual/pub1484423
PMID
34055377
Source
pubmed
Published In
Neuro Oncology Practice
Volume
8
Published Date
Start Page
299
End Page
309
DOI
10.1093/nop/npaa084

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