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Last Updated: 09/21/21

SPORE for Translational Approaches to Brain Cancer

Northwestern University

Principal Investigator(s):

Maciej S. Lesniak, MD
Maciej S. Lesniak, MD

Principal Investigator(s) Contact Information

Maciej S. Lesniak, MD
Department of Neurological Surgery
Northwestern University
676 N. St Clair, Suite 2210
5841 South Maryland Ave.
Chicago, IL 60611
Phone: (312) 695-6200

Overview

The Northwestern Brain Tumor SPORE is dedicated to improving treatment outcomes for patients afflicted with highly malignant brain tumors, with particular emphasis on glioblastoma (GBM). This will be accomplished through the efforts of a talented group of investigators whose complementary expertise will be combined in a team science approach that will accelerate progress in the identification of effective therapies for GBM.

Project 1: Neural stem cell based oncolytic virotherapy of malignant glioma

Project Co-Leaders:
Maciej S. Lesniak, MD
Atique U. Ahmed, PhD
Irina V. Balyazsnikova, PhD
Roger Stupp, MD

Oncolytic virotherapy (OV) is a novel modality of anti-cancer therapy, which consists of using genetically engineered conditionally replicating virus to target and destroy cancer cells. Such selectivity of viral replication is achieved by employing various strategies including transcriptional targeting where tumor selective expression is used to drive virus replication and capsid modifications that promotes tumor specific binding of the therapeutic virus. Our team has developed a dual targeted oncolytic virus, CARd-Survivin-pK7 (CARd-S-pk7), and extensively evaluated this virus for the treatment of malignant glioma. In preclinical research, CRAd-S-pk7 exhibits extensive anti-tumor activity in mice bearing intracranial human glioma xenografts, including the highly aggressive CD133+ glioma stem cell population, and cooperates with conventional anti-glioma chemo- and radiotherapy.

One of the major limitations of OV therapy has been poor intratumoral distribution. To overcome this problem our group has demonstrated that neural stem cells (NSCs) can be used as a virus producer to enhance viral delivery. This form of carrier cell based OV enhances viral distribution throughout the tumor, which results in a much more potent anti-tumor response than local delivery of OV alone. Based on this work, we are now translating this therapeutic approach to the clinical setting, and are in the midst of conducting a clinical trial to test cell based OV treatment in glioma patients. The immediate goal of this SPORE project is to evaluate the safety of NSCs-CRAd-S-pk7 as a therapeutic platform for patients with malignant glioma.

Our specific aims are

Specific Aim 1: Evaluate clinical responses in patients administered CRAd-S-pK7-loaded NSCs.

Specific Aim 2: Investigate immune response in patients administered NSCs carrying CRAd-S-pK7.

Specific Aim 3: Use imaging to assess cell distribution and tumor response to NSCs-CRAd-S-pK7 treatment.

Project 2: Simultaneous radiotherapy with PD-1 and IDO1 blockade for overcoming immune suppression in glioblastoma

Project Co-Leaders:
Derek Wainwright, PhD
Charles David James, PhD
Rimas Lukas, MD

Immunotherapy carries great promise for the treatment of several solid tumors, including malignant glioma. However, in order to have impact on immunotherapy treatment outcomes, a multimodal treatment approach is likely required. For GBM, a heterogeneous tumor characterized by local immunosuppression and an immune-privileged environment, a combination of radiotherapy with concomitant immunomodulation by an immune checkpoint inhibitor as well as an inhibitor of an immunosuppressive enzymatic activity could prove effective. We have used this approach in preclinical research and shown this triple therapy results in a durable survival benefit to mice with intracranial GBM. These preclinical findings will be translated to a clinical trial for patients with newly diagnosed GBM. The interpretation of treatment outcomes will be aided by the incorporation of a-[11C]-methyl-L-Trp (AMT)-PET imaging, which is a noninvasive method to quantifying IDO1 activity that is responsible for producing an immunosuppressive metabolite, and by a comprehensive immunmonitoring assay panel. In parallel, we will conduct further experiments with mice reconstituted with human immune function and inoculated with tumors of human origin (PDX), for testing additional therapeutics that can be incorporated in future clinical trials that are derivatives of the initial trial proposed here. Our specific aims for this project are:

Specific Aim 1: Conduct a phase I/IIa study of RT with concurrent checkpoint (PD-1 mAb) and IDO1 enzyme inhibition in patients with newly diagnosed, MGMT-unmethylated GBM.

Specific Aim 2: Evaluate intratumoral IDO1 activity with AMT-PET in GBM patients receiving treatment with concurrent RT + PD-1 mAb + IDO1 inhibitor.

Specific Aim 3: Characterize GBM and immune response to RT, PD-1 mAb and IDO1 enzyme inhibition.

Project 3: Using RNAi-based spherical nucleic acid (SNA) nanoconjugates targeting Bcl2L12 to promote therapy-induced apoptosis in glioblastoma

Project Co-Leaders:
Alexander Stegh, PhD
Priya Kumthekar, MD

Glioblastoma (GBM), the most aggressive and prevalent manifestation of malignant glioma, is characterized by resistance to extant therapeutic modalities, and exhibits a neurologically debilitating course culminating in death, most often within 14 months after diagnosis. The biggest challenge to improving GBM patient outcomes has been the identification and characterization of new drug targets and the development of drug delivery platforms to target previously undruggable genetic lesions. Restoration of p53 activity represents an attractive therapeutic strategy for the treatment of GBM, as ~65% of primary GBM patients express wildtype, but functionally suppressed p53. Amplification and overexpression of the atypical Bcl2 family protein Bcl2L12 (Bcl2-Like-12) compromises p53 function by blocking the transcriptional activity of p53. To inhibit Bcl2L12 function we have used novel RNAi-based nanoconjugates, termed Spherical Nucleic Acids (SNAs), to neutralize Bcl2L12 expression in established GBM. We have found that Bcl2L12-targeting SNAs (siBcl2L12-SNAs) are able to traverse cellular membranes including the blood-brain-barrier. We established that siBcl2L12-SNAs do not require the use of toxic auxiliary reagents and accumulate effectively in GBM tumor cells upon crossing the blood-brain/blood-tumor barrier in intracerebral GBM xenografts following systemic administration of the SNAs. SNAs exhibit stability in physiological environments, provoke robust intratumoral Bcl2L12 mRNA and protein knockdown resulting in p53 reactivation, and slow tumor growth in GBM patient derived xenograft (PDX) models. Here, we will further investigate the hypothesis that Bcl2L12 suppression by SNA treatment increases p53 tumor suppressor activity, slows GBM progression, and can be combined with conventional genotoxic therapies as well as with targeted therapeutics for improving GBM treatment outcomes.

We propose three specific aims:

Specific Aim 1: Determine siBcl2L12 treatment effect in patient-derived glioma-initiating cells (GICs) in vitro, and in PDX models in vivo, when used as monotherapy and in combination with radiation therapy (RT).

Specific Aim 2: Using both PDX models for newly diagnosed and recurrent tumor, together with syngeneic, immunocompetent mouse models, we will combine siBcl2L12 with cytotoxic and p53-activating chemotherapeutic drugs, i.e., the DNA alkylator temozolomide and the MDM2 inhibitor RG7388, respectively.

Specific Aim 3: Conduct a phase 0 clinical trial of siBcl2L12-SNAs, to determine SNA pharmacokinetics, biodistribution, and ability to downregulate GBM-associated Bcl2L12 mRNA and protein in patients.

Project 5: A phase 1 adaptive dose-escalation study of mycophenolate mofetil (MMF) in combination with temozolomide (TMZ) for patients with newly diagnosed glioblastoma

Project Co-Leaders:
Atique Ahmed, PhD (Basic Science Co-leader)
Roger Stupp, MD (Basic Science Co-leader)
Priya Kumthekar, MD (Basic Science Co-leader)

Glioblastoma (GBM), a grade IV tumor, is one of the most aggressive and infiltrative brain cancer forms. Patients that are currently diagnosed with Glioblastoma (GBM) have an abysmal prognosis. The median survival is around 8-10 months, even after the standard care protocol of surgical resection followed by alkylating chemotherapy (typically temozolomide or TMZ) and radiotherapy. This is because, in nearly all patients, the tumor recurs after treatment since GBM cells can become resistant to therapy. Our laboratory's goal is to develop a treatment for GBM that will reduce the recurrence rate and improve the prognosis for patients. One of the distinguishing characteristics of cancer is its uncontrolled cell division. Since cancer cells divide more rapidly than normal cells, they require more purines, DNA, and RNA building blocks. Purines are either synthesized from amino acids and other small molecules through the de novo biosynthesis pathway or are recycled from the microenvironment through the salvage pathway. Cancer cells typically use the de novo biosynthesis pathway, whereas the central nervous system usually relies more on the salvage pathway. We have identified ARL13B as a novel regulator of the purine biosynthesis pathway during chemotherapy through initial analysis. ARL13B, a member of the ADP-ribosylation factor-like family protein accountable for cilia maintenance, directly interacts with inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme purine biosynthesis. Our initial studies knocking down ARL13B inhibited GBM cells' utilization of the de novo pathway after TMZ treatment and increased utilization of the salvage biosynthesis pathway. The effectiveness of TMZ treatment was also elevated in vitro and in vivo following ARL13B knockdown. We, therefore, proposed that the ARL13B-IMPDH2 regulated switch from the salvage pathway to the de novo purine biosynthesis pathway is necessary for GBM cells' adaptation to alkylating-based chemotherapy. Based on this, we hypothesize that therapeutic transformation in GBM involves interaction between ciliary protein ARL13B and rate-limiting purine biosynthesis enzyme IMPDH2 Mycophenolate mofetil (MMF), an FDA-approved drug in the organ-transplant setting, inhibits IMPDH2 activity and allows for increased the therapeutic efficacy of TMZ and extended the survival of patient-derived xenograft (PDX) models across multiple GBM subtypes. This provides a clinically translatable opportunity to overcome chemoresistance in GBM.

In this proposal, we propose to conduct a Phase 1/1b clinical trial of MMF combined with standard chemo- and radiotherapy for newly diagnosed GBM. The specific aims are:

Specific Aim 1: To evaluate this novel combination's safety and toxicity and establish the maximally tolerated dose (MTD).

Specific Aim 2: To evaluate exploratory secondary endpoints including progression-free and overall survival. Additionally, we will investigate mycophenolic acid, an immediate metabolite of MMF that can serve as a biomarker for such therapy.

Administrative Core

Core Directors:
Maciej S. Lesniak, MD
Charles David James, PhD

The SPORE Administrative Core will provide the structure and oversight that facilitates scientific productivity and innovation, and promotes collaborative activities for SPORE investigators. Through its functions and activities, this Core will serve as the central organizational hub for the Projects and Cores, and will assist investigators in achieving their translational research objectives. The Administrative Core ensures that the SPORE is fully integrated into the administrative structure of the Robert H. Lurie Comprehensive Cancer Center (LCC) at Northwestern. The Administrative Core will provide the organizational leadership that is needed by all components of the SPORE, through activities associated with the following specific aims:

Specific Aim 1: Integrate the SPORE within the activities of the Lurie Cancer Center and Feinberg School of Medicine.

Specific Aim 2: Develop, maintain and, as needed, modify the External Advisory and Internal Advisory Boards and Executive committee that provide advice to, as well as oversight of, SPORE research.

Specific Aim 3: Organize and conduct bi-weekly research meetings for frequent evaluation of SPORE progress.

Specific Aim 4: Provide fiscal planning for and oversight of all components of this SPORE.

Specific Aim 5: Organize and conduct patient advocacy activities.

Specific Aim 6: Facilitate collaborations with investigators at the LCC, other SPORE institutions, industry, and with other funded programs.

Biospecimen Core

Core Directors:
Craig M. Horbinski, MD
Daniel J. Brat, MD

The Biospecimen Core is a vital resource that supports all brain tumor research at Northwestern, and is especially important in seeing that all projects experience clinical translation within the period of SPORE funding. Regular interactions with the Biostatistics & Bioinformatics Core and Administrative Core will ensure that each project achieves its objectives, and has positive impact on the care of brain tumor patients.

The Biospecimen Core will have extensive interactions with all projects and cores by acting as the central repository of patient tissues and renewable tumor resources, by providing the highest quality of tissue analytical services, and by providing neuropathological consultation. The Director of the Core, Dr. Horbinski, as well as the Co-Director, Dr. Daniel Brat, will supervise quality control testing of banked specimens, and will perform all microscopy-based analyses of patient tissues and tumor models for each SPORE project. Biospecimen Core activities will see to the following:

Specific Aim 1: Provide Northwestern brain tumor researchers with annotated biospecimens from brain tumor patients.

Specific Aim 2: Subject all biospecimens to rigorous quality control.

Specific Aim 3: Propagate, bank, and characterize surgical specimen derivatives, including PDX and cancer stem cell (CSC) models, to meet ongoing needs for renewable tumor cell sources.

Specific Aim 4: Support SPORE projects with neuropathologic consultation and analyses.

Biostatistics and Bioinformatics Core

Core Directors:
Denise Scholtens, PhD
Elizabeth Bartom, PhD

The Biostatistics and Bioinformatics Core (B&B Core) is a central component of the Brain Tumor SPORE, and provides state-of-the-art integrated data science support to all Brain Tumor SPORE projects. Database development and maintenance will provide a centralized resource for data tracking for preclinical studies, ensuring efficient reporting and statistical analysis of all experiments. In addition, clinical databases will be developed in conjunction with all project teams to complement existing clinical trial data registries at Northwestern and ensure custom data capture in a highly secure environment. Bioinformatics activities of the B&B Core are central to discovery and will help define new and significant research directions. The large omics data sets that will be generated in the Brain Tumor SPORE Projects require specialized expertise for preprocessing, analysis and interpretation of molecular and biological consequences of genetic manipulations and treatments. Bioinformatics service provided by the B&B Core will contribute to the productivity of all SPORE research, and contribute to project goals being achieved. Biostatistical activities of the B&B Core are central to the concerns of rigor and reproducibility: by providing study design guidance, data management, statistical analysis and consultation for interpretation of results the core will see that reported results have been rigorously controlled and will be reproducible by others. All functions of the B&B Core will be conducted in association with the following specific aims:

Specific Aim 1: Establish and maintain database functionality for all preclinical and clinical data.

Specific Aim 2: Provide bioinformatics collaboration and support for pre-processing and analysis of high-dimensional omics data, including array-based and sequencing data.

Specific Aim 3: Provide biostatistical collaboration and support for design of preclinical studies and clinical trials, as well as statistical analyses of all data. Through these activities the B&B Core will serve as a key contributor to all individual projects and will ensure that project output is accurate, reliable, and of the highest quality.

Developmental Research Program

This program provides seed funds to support innovative, high-impact, translational cancer research projects.

Career Enhancement Program

This program provides seed funding to nurture investigators interested in translational cancer research.