Glioblastoma (GBM) is one of the most common, deadly, and difficult-to-treat adult brain tumors. Surgical removal of the tumor, followed by radiotherapy (RT) and temozolomide (TMZ) administration, is the current treatment modality, but this regimen only modestly improves overall patient survival. Invasion of cells into the surrounding healthy brain tissue prevents complete surgical resection and complicates treatment strategies with the goal of preserving neurological function. Despite significant efforts to increase our understanding of GBM, there have been relatively few therapeutic advances since 2005 and even fewer treatments designed to effectively treat recurrent tumors that are resistant to therapy. Thus, while there is a pressing need to move new treatments into the clinic, emerging evidence suggests that key features unique to GBM location and biology, the blood-brain barrier (BBB) and intratumoral molecular heterogeneity, respectively, stand as critical unresolved hurdles to effective therapy. Notably, genomic analyses of GBM tissues has led to the identification of numerous gene alterations that govern cell growth, invasion and survival signaling pathways; however, the drugs that show pre-clinical potential against signaling pathways mediated by these gene alterations cannot achieve effective concentrations at the tumor site. As a result, identifying BBB-penetrating drugs and utilizing new and safer methods to enhance drug delivery past the BBB has become an area of intensive research. Repurposing and combining FDA-approved drugs with evidence of penetration into the central nervous system (CNS) has also seen new interest for the treatment of both primary and recurrent GBM. In this review, we discuss emerging methods to strategically enhance drug delivery to GBM and repurpose currently-approved and previously-studied drugs using rational combination strategies.
Background Tumor heterogeneity underlies resistance and disease progression in glioblastoma (GBM), and tumors most commonly recur adjacent to the surgical resection margins in contrast non-enhancing (NE) regions. To date no targeted therapies have meaningfully altered overall patient survival in the up-front setting. The aim of this study is to characterize intratumoral heterogeneity in recurrent GBM using bulk samples from primary resection and recurrent samples taken from contrast-enhancing (EN) and contrast non-enhancing (NE) regions. Methods Whole exome and RNA sequencing were performed on matched bulk primary and multiple recurrent EN and NE tumor samples from 16 GBM patients who received standard of care treatment alone or in combination with investigational clinical trial regimens. Results Private mutations emerge across multi-region sampling in recurrent tumors. Genomic clonal analysis revealed increased enrichment in gene alterations regulating the G2M checkpoint, Kras signaling, Wnt signaling, and DNA repair in recurrent disease. Subsequent functional studies identified augmented PI3K/AKT transcriptional and protein activity throughout progression, validated by phospho-protein levels. Moreover, a mesenchymal transcriptional signature was observed in recurrent EN regions, which differed from the proneural signature in recurrent NE regions. Conclusions Subclonal populations observed within bulk resected primary GBMs transcriptionally evolve across tumor recurrence (EN and NE regions) and exhibit aberrant gene expression of common signaling pathways that persist despite standard or targeted therapy. Our findings provide evidence that there are both adaptive and clonally-mediated dependencies of GBM on key pathways, such as the PI3K/AKT axis, for survival across recurrences.
Esophageal adenocarcinoma (EAC) has seen a 400% increase in incidence over the past 30 years. The 5-year survival rate is under 20% due to ineffective therapeutics and a lack of actionable oncogenic drivers, necessitating novel therapeutic avenues in this disease. Genomic analysis indicates that a subset of EAC tumors have alterations in the G2/M cell cycle check point and DNA damage response governed by mutations in TP53 or other hits in this pathway, suggesting targeting the G2/M pathway might be a viable option in EAC. We and others have demonstrated that the WEE1 inhibitor AZD1775 is effective both in vitro and in vivo against tumors with DNA damage response alterations, and this drug is currently in clinical trials across a number of tumor types. We hypothesized that inhibition of WEE1 would induce DNA damage and cell death in EAC tumors, and provide a rational therapeutic avenue against this deadly disease. Across multiple EAC cell lines, AZD1775 suppressed tumor cell growth either as a monotherapy or in combination with DNA-damaging therapies. The growth suppression was accompanied by persistent DNA damage as determined by γH2AX and the induction of apoptosis. FLO-1 cells, responsive to monotherapy AZD1775, showed a dramatic reduction in G2 cells 24 hours post AZD1775 exposure with concomitant increases in cells in G0 and S phases of the cycle; while SK-GT-4, resistant to monotherapy AZD1775, showed an initial reduction in cells in G2 but recovered to normal levels 24 hours post-exposure. To assess AZD1775 in vivo, we generated a patient-derived xenograft (PDX) model of an EAC tumor excised at our institution. Combinations of AZD1775 with radiation or cisplatin significantly reduced in vivo tumor growth compared to vehicle, and the combination of AZD1775 with cisplatin was as effective as standard-of-care treatment (cisplatin + docetaxel + radiation), a therapeutic avenue plagued by toxicity in humans. Exposure to AZD1775 in combination with cisplatin showed suppression of phospho-CDC2 (target-hit) and induction of γH2AX in vivo compared to vehicle. Towards understanding a mechanism for lack of response of certain EAC cell lines to AZD1775 monotherapy, we explored the PI3K pathway that has been previously implicated in AZD1775 resistance. SK-GT-4 cells, which are unresponsive to AZD1775 monotherapy, demonstrated elevated phospho-AKT and phospho-p70S6K protein levels compared to other cell lines and were found more sensitive to PI3K or MTOR inhibition, suggesting a dependence on this pathway for tumor cell survival. Collectively, our data suggest that AZD1775, both alone and in combination with standard-of-care DNA damage, may be an effective therapeutic strategy for those EAC tumors dependent on the G2/M checkpoint. Citation Format: Mylan Blomquist, Vashti M. Carson, Ross M. Bremner, Timothy G. Whitsett, Landon J. Inge. WEE1 inhibition suppresses esophageal adenocarcinoma tumor growth both in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1526.
Glioblastoma (GBM), the most common primary brain tumor in adults, remains uniformly fatal due to the lack of effective targeted therapies for this aggressive malignancy. Genomic amplification of epidermal growth factor receptor (EGFR) occurs in 40-60% of primary GBM. Half of all EGFR-amplified cases of GBM also harbor EGFRvIII, a constitutively active, truncated variant of EGFR. The incidence of EGFR alterations in GBM makes inhibition of EGFR/EGFRvIII an attractive therapeutic approach. Depatuxizumab mafodotin (ABT-414) is an antibody-drug conjugate comprised of ABT-806, a mAB against EGFR, and a cytotoxic payload (monomethyl auristatin F). ABT-414 therapy initially showed promising results as an EGFRvIII therapy in vivo and in vitro; however, ABT414 failed to provide a survival benefit in phase I/II clinical trials, potentially due to therapeutic resistance. In this study, we seek to investigate the mechanisms of resistance to ABT-414 by performing whole exome, transcriptome and single cell RNA seq on ABT-414 resistant GBM PDX tumors. Our data showed an enrichment of mutations unique to the ABT-414 resistant tumors, including a point mutation (S466I) in TEK/TIE2 transmembrane angiopoietin receptor. In vitro expression of TEK S466I in GBM cells showed an increase in activation of ERK and STAT3 and increased TEK/TIE2 immunoprecipitation with EGFR compared to the wild-type TEK receptor. Furthermore, gene ontology analysis reveals that ABT-414-treated flank tumors exhibit increased activation of extracellular matrix organization and CNS developmental processes compared to flank tumors in the control treatment groups. ABT-414-treated tumors also demonstrate increased expression of inhibitor of differentiation (ID)1 and ID3, associated with stem-like phenotype in glioblastoma. Taken together, our data indicate that resistance to ABT-414 is mediated by both de novo mutations not detected in the parent tumor and adaptive dysregulation of pathways which may lead to dedifferentiation and therapeutic resistance.
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