Development of new treatments for rare CNS tumors

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

'OBJECTIVE 1. Examine the role of topoisomerase inhibition in targeting the alterations in DNA repair and hypercoiling in MYC and MYCN amplified CNS tumors. - PROGRESS: Recently, a new subtype of ependymoma characterized by MYCN amplification was discovered based on collaborative efforts between NOB investigators and the NCI Laboratory of Pathology, along with the work of other colleagues in Germany. This is a highly aggressive cancer, refractory to most established treatments, and driven by a molecular alteration that has been considered undruggable. Although medulloblastoma is a tumor considered rare in adults, 30% of all cases are diagnosed in late teenagers and young adults under the age of 40. Recurrent medulloblastoma is considered uncurable, and adults commonly do not have access to pediatric clinical trials. Combined MYC family amplifications and P53 pathway defects emerge in 32% of relapsed medulloblastomas. I have started a search for novel therapies for MYCN-amplified ependymoma, MYC or MYCN-amplified medulloblastoma, and other primary CNS tumors sharing the same molecular alteration, collaborating with other NIH investigators. We plan to exploit the DNA supercoiling that results from MYC and MYCN amplification. I lead an investigator-initiated, IND Phase I/II clinical trial using a Pegylated form of SN38 (PLX038) to test efficacy and predictive markers. This trial incorporates a novel Phase I design (time-to-event Bayesian optimal interval, TITE-BOIN) to shorten the trial duration and reduce the logistic difficulties caused by repeatedly suspending accrual. The Phase II component will incorporate correlatives at 3 timepoints: archival or baseline tissue before starting therapy, post cycle 2, and at the time of tumor progression. The protocol is currently undergoing IRB review. 'OBJECTIVE 2. Examine the role of maintenance smoothened inhibition in adult patients with medulloblastoma (MB) and activation of the Sonic Hedgehog pathway (SHH-MB subgroup). - PROGRESS: Unlike MB in children, robust prospective trials have not taken place for older patients. Clinical and molecular classification of MB now provides better prognostication and is being incorporated in pediatric therapeutic trials. It has been established that genomic alterations leading to activation of the SHH pathway occur in approximately 60% of MB in patients over the age of 16 years. Within this cohort, protein patched homolog (PTCH) and smoothened (SMO) mutations are commonly found. Among patients whose tumors harbor the SHH molecular signature, it is estimated that over 80% of patients could respond to SHH pathway inhibitors. The Alliance for Clinical Trial in Oncology group developed the AMBUSH trial: Comprehensive Management of AYA and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors with a Randomized Placebo-Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial) (PI: Anita Mahajan, Radiation Oncologist Mayo Clinic). This trial will enroll patients 18 years of age or older with MB (any molecular subgroup and risk stratification) or pineal embryonal tumor. Patients will be assigned to one of three cohorts: (1) average risk non-SHH-MB, (2) average risk SHH-MB, and (3) high-risk MB or pineal embryonal tumors. All patients will receive protocol-directed comprehensive treatment with radiation therapy and chemotherapy. Patients with SHH-MB in cohort 1 will be randomized to a smoothened inhibitor or placebo as maintenance therapy for one year. As the Neuro-Oncology Co-Chair for this cooperative study, which is currently undergoing regulatory approval, I have participated in all aspects of study design. 'OBJECTIVE 3. Examine the role of immunotherapy in treating patients with Rare CNS Tumors. - PROGRESS: To date, there is little evidence that immune checkpoint treatment is effective in most patients with primary CNS tumors. Various factors have been postulated including an immune-suppressive tumor microenvironment and systemic immunosuppression that is either iatrogenic (corticosteroids, chemotherapy) or produced by the cancer (ie TGF-B). My actively accruing multicenter basket clinical trial (NCT 03173950) is enrolling patients with selected recurrent rare CNS cancers who have completed prior standard therapies across 10 participating centers in the US, with NOB being the leading site. Participants receive nivolumab for up to 16 cycles. The primary efficacy endpoint is disease control rate (DCR; partial responses, complete responses, or stable disease for at least 6 months). Extensive monitoring of immune response in peripheral blood is done longitudinally. Immune cell phenotyping, cell function, and plasma chemokines and cytokines will be measured on these samples. Additional future studies will include the correlation of changes in immunity with survival and the development and resolution of immune-related toxicities and changes in participants' symptoms and function. Future plans also include determining if certain tumor types or molecular subgroups are more susceptible to checkpoint inhibitor therapy, as well as elucidating potential mechanisms of resistance to set the rationale for subsequent clinical trials for patients with specific diagnoses or baseline biomarkers. The trial enrolls patients in two different cohorts (Cohort 1: heaviliy pretreated and Cohort 2: non-heavily pretreated), exploring the hypothesis of differential effect based on extent of prior treatment and asking the question of whether heavy pretreatment limits the immune response or increases the tumor mutational burden thus favoring a response. Cohort 1 has completed full accrual in July 2023 (n=75) and Cohort 2 has reached the preplanned accrual for interim efficacy analysis. 'OBJECTIVE 4. Discover gaps in knowledge in the care and treatment of patients with Rare CNS Tumors. - PROGRESS: The World Health Organization (WHO) classification of primary CNS tumors includes more than 130 tumor types with varying clinical behavior and outcome. Most brain and spine neoplasms have an annual incidence of less than 1,000 cases per year in the US. Given the rarity of these tumors, there is limited understanding of their natural history and molecular makeup and a paucity of proven therapies. In collaboration with the pathology team, I launched a multicenter study across the BTTC/CONNECT consortium to collect tumor tissue and structured clinical information in deceased and lost to follow-up adults with rare CNS tumors. The study's objectives are: 1) to study the clinical course of adult patients with select rare CNS tumors included under the NCI-CONNECT program. This will include analyzing the impact of patient, tumor, and therapy-related factors and correlate with outcome (progression-free interval and overall survival), and 2) identifying clinically relevant molecular markers in previously collected tumor tissue that define molecular subtypes, response to therapy and high-risk molecular signatures for aggressive clinical behavior of rare CNS tumors in adults. Molecular analysis and clinical data abstraction of around 100 cases from 6 different collaborating institutions is currently underway. Starting in 2020, the weekly multidisciplinary NIH Neuro-Oncology Tumor Board was transitioned to a virtual format and expanded to include NCI-CONNECT consortium sites and neighbor institutions in the area NIH geographic area under my leadership. In collaboration with the information technology team, I am leading the development of a database to assist with the logistics of the tumor board, serve as an educational repository of cases and allow interrogation of the database for research purposes