Our new Journal of Clinical Investigation paper using patient-specific mathematical modeling to prove efficacy of a novel gene therapy of glioblastoma



Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

Jennifer E. Adair1,2, Sandra K. Johnston3, Maciej M. Mrugala4,5, Brian C. Beard1,2, Laura A. Guyman6,7, Anne L. Baldock6,7, Carly A. Bridge6,7, Andrea Hawkins-Daarud6,7, Jennifer L. Gori1, Donald E. Born8, Luis F. Gonzalez-Cuyar9, Daniel L. Silbergeld3,9, Russell C. Rockne6,7, Barry E. Storer1,10, Jason K. Rockhill3,11, Kristin R. Swanson6,7,12 and Hans-Peter Kiem1,2,9

1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 2Department of Medicine, 3Department of Radiology, 4Department of Neurosurgery, and 5Department of Neurology, University of Washington (UW), Seattle, Washington, USA. 6Department of Neurological Surgery and 7Northwestern Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 8Department of Pathology, Stanford University, Stanford, California, USA. 9Department of Pathology, 10Department of Biostatistics, and 11Department of Radiation Oncology, UW, Seattle, Washington, USA. 12Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Address correspondence to: Hans-Peter Kiem, Fred Hutchinson Cancer Research Center, Mail Stop D1-100, P.O. Box 19024, Seattle, Washington 98109-1024, USA. Phone: 206.667.4425; E-mail: hkiem@fhcrc.org.

Published August 8, 2014 Received for publication April 29, 2014, and accepted in revised form July 1, 2014.

BACKGROUND. Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMThi). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome.

METHODS. We enrolled 7 newly diagnosed glioblastoma patients with MGMThi tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O6BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated.

RESULTS. Gene therapy permitted a significant increase in the mean number of tolerated O6BG/TMZ cycles (4.4 cycles per patient, P < 0.05) compared with historical controls without gene therapy (n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5–57+) months and OS of 20 (range 13–57+) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O6BG.

CONCLUSION. These data support further development of chemoprotective gene therapy in combination with O6BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT.

TRIAL REGISTRATION. Clinicaltrials.gov NCT00669669.

FUNDING. R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970.

Written on August 8th, 2014. 0 Comments

See Kristin Swanson’s TEDxUChicago Talk

Written on August 8th, 2014. 0 Comments

Lab receives James S. McDonnell Foundation grant for The “ENDURES” Study: ENvironmental Dynamics Underlying Responsive Extreme Survivors of Glioblastoma

Written on July 23rd, 2014. 0 Comments

MNO Lecture Series: July 28th 2014 – Jasmine Foo, Ph.D. and Kevin Leder, Ph.D.

The Mathematical Neuro-Oncology Research Lab Presents:


Monday, July 28th, 2014
1:30 – 2pm
Arkes Pavilion
676 N. Saint Clair St. Suite 1300
Assistant Professor of Mathematics
The University of Minnesota
Title: Hitchhiking Index: Identifying driver and passenger mutations in cancer
Bio: Jasmine Foo is an McKnight Land Grant assistant professor at the University of Minnesota math department. She completed her PhD in Applied Math at Brown University in 2008, and carried out postdoctoral work at Harvard University/Dana Farber Cancer Center and the Memorial Sloan Kettering Cancer Center. Her research involves using stochastic processes to formulate and analyze mathematical theories of cancer evolution.
Abstract: The traditional view of cancer as a genetic disease that can successfully be treated with drugs targeting mutantoncoproteins has motivated whole-genome sequencing efforts in many human cancer types. However, only a subset of mutations found within the genomic landscape of cancer is likely to provide a fitness advantage to the cell. Distinguishing such “driver’ mutations from innocuous “passenger” events is critical for prioritizing the validation of candidate mutations in disease-relevant models. Here we propose a novel statistical index, called the Hitchhiking Index, which reflects the probability that any observed candidate gene is a passenger alteration, given the frequency of alterations in a cross-sectional cancer sample set. Our methodology is based upon a evolutionary population-dynamics model of mutation accumulation and selection in the tissue prior to cancer initiation as well as during tumorigenesis.

Monday, July 28th, 2014
2:30 – 3pm
Arkes Pavilion
676 N. Saint Clair St. Suite 1300

Assistant Professor of Industrial and Systems Engineering The University of Minnesota
Title: Mathematical Modeling and OptimalFractionationated Irradiation for Proneural Glioblastomas
Bio: Dr. Leder is an assistant professor in Industrial and Systems Engineering at University of Minnesota.
He is interested in stochastic process models of cancer evolution, and the use of these models to investigate important biological questions regarding the initiation, progression and treatment of cancer. In addition he is interested in the study of rare events in stochastic systems. Previously, he was a postdoc at Dana Farber Cancer Institute and the Department of Industrial Engineering and Operations Research at Columbia, and received his PhD in 2008 from the Department of Applied Mathematics at Brown University. As an undergraduate, he attended the University of Colorado at Boulder and majored in Applied Math.
Abstract: Glioblastomas (GBM) are the most common and malignant primary tumors of the brain and are commonly treated with radiation therapy. Despite modest advances in chemotherapy and radiation, survival has changed very little over the last 50 years. Radiation therapy is one of the pillars of adjuvant therapy for GBM but despite treatment, recurrence inevitably occurs. Here we develop a mathematical model for the tumor response to radiation that takes into account the plasticity of the hierarchical structure of the tumor population. Based on this mathematical model we develop an optimized radiation delivery schedule. This strategy was validated to be superior in mice and nearly doubled the efficacy of each Gray of radiation administered. Time permitting I will also discuss recent extensions of this work that consider the impact of including normal tissue toxicity constraints. This is based on joint work with Hamidreza Badri, Ken Pitter, Eric Holland, and Franziska Michor.

Written on July 23rd, 2014. 0 Comments

Lab receives James S. McDonnell Foundation grant for The “ENDURES” Study: ENvironmental Dynamics Underlying Responsive Extreme Survivors of Glioblastoma

Written on July 23rd, 2014. 0 Comments

November/December 2013 – Congratulations to Mr. Rosenberg on his new paper in Missouri Medicine

pgs 517-523

Written on May 22nd, 2014. 0 Comments

Congratulations to Ms. Baldock and the team! IDH1 paper receives kudos in an editorial in NeuroOncology! (Published April 15, 2014)

The Article made the cover of June 2014 Issue!


Written on May 22nd, 2014. 0 Comments

Lab receives Dixon Translational Research Grant for Patient-Specific Mathematical Modeling of Pediatric High Grade Gliomas


Written on May 22nd, 2014. 0 Comments

MNO Lecture Series: April 14th 2014 – Jacob G. Scott MD

The Mathematical Neuro-Oncology Research Lab Presents:

Departments of Radiation Oncology and Integrated Mathematical Oncology
H. Lee Moffitt Cancer Center

Mathematical modeling of glioma cancer stem cell evolutionary dynamics and the non-genetic determinants of the metastatic process

Monday, April 14th, 2014
11am – 12 noon
Arkes Pavilion,
676 n. Saint Clair St. Suite 1300
Mathematical Neuro-Oncology Lab

Jacob Scott is a research associate in the department of radiation oncology at H. Lee Moffitt Cancer Center in Tampa Florida and is currently working on a Doctoral degree in mathematics at Oxford University at the Centre for Mathematical Biology. Dr. Scott began his academic career in the fields of physics and engineering before entering medical school. As a trained clinician and scientist, Dr. Scott pursues a combination of basic and clinical research with the hope that each motivates and strengthens the other.

The focus of Dr. Scott’s research is building theoretical models of cancer with Integrative Mathematical Oncology – a group headed by Alexander (Sandy) Anderson, Ph.D. that focuses on applying mathematical and evolutionary models to the study of cancer. Dr. Scott finds that spending time doing a combination of theoretical cancer research and patient care keeps him thinking outside the box in the clinic, but keeps theoretical questions grounded to ideas that can be translated to patient care.

Dr. Scott is active in social media. Follow him on twitter at

Written on April 9th, 2014. 0 Comments

Congratulations to Dr. Hawkins-Daarud on her new paper in Frontiers in Oncology

Modeling tumor-associated edema in gliomas during anti-angiogenic therapy and its impact on imageable tumor

  • 1Department of Neurological Surgery, Northwestern University, Chicago, IL, USA
  • 2Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA

Glioblastoma, the most aggressive form of primary brain tumor, is predominantly assessed with gadolinium-enhanced T1-weighted (T1Gd) and T2-weighted magnetic resonance imaging (MRI). Pixel intensity enhancement on the T1Gd image is understood to correspond to the gadolinium contrast agent leaking from the tumor-induced neovasculature, while hyperintensity on the T2/FLAIR images corresponds with edema and infiltrated tumor cells. None of these modalities directly show tumor cells; rather, they capture abnormalities in the microenvironment caused by the presence of tumor cells. Thus, assessing disease response after treatments impacting the microenvironment remains challenging through the obscuring lens of MR imaging. Anti-angiogenic therapies have been used in the treatment of gliomas with spurious results ranging from no apparent response to significant imaging improvement with the potential for extremely diffuse patterns of tumor recurrence on imaging and autopsy. Anti-angiogenic treatment normalizes the vasculature, effectively decreasing vessel permeability and thus reducing tumor-induced edema, drastically altering T2-weighted MRI. We extend a previously developed mathematical model of glioma growth to explicitly incorporate edema formation allowing us to directly characterize and potentially predict the effects of anti-angiogenics on imageable tumor growth. A comparison of simulated glioma growth and imaging enhancement with and without bevacizumab supports the current understanding that anti-angiogenic treatment can serve as a surrogate for steroids and the clinically driven hypothesis that anti-angiogenic treatment may not have any significant effect on the growth dynamics of the overall tumor cell populations. However, the simulations do illustrate a potentially large impact on the level of edematous extracellular fluid, and thus on what would be imageable on T2/FLAIR MR. Additionally, by evaluating virtual tumors with varying growth kinetics, we see tumors with lower proliferation rates will have the most reduction in swelling from such treatments.



Written on September 11th, 2013. 0 Comments