Glioblastoma Multiforme (GBM) is the most common malignant primary brain tumor. Despite aggressive multimodality treatment it remains one of the most challenging and intractable cancers (1]. While current standard of care treatment for GBM is maximal safe surgical resection, systemic chemotherapy with Temozolimide (TMZ), and radiation therapy, the current prognosis of GBM patients remains poor, with a median overall survival of 12-15 months (2, 3). Therefore, other treatments are needed to provide better outcomes for GBM patients. Immunotherapy is one of the most promising new cancer treatment approaches. Immunotherapy drugs have obtained regulatory approval in a variety of cancers including melanoma (4), Hodgkin lymphoma (5), and non-small cell lung cancer (6). The basis of immunotherapy in cancer treatment is linked to stimulating the immune system to recognize cancer cells as foreign, thereby leading to the eventual elimination of the tumor. One form of immunotherapy utilizes vaccines that target tumor antigens (7), while other approaches utilize T-cells in patients to stimulate them to attack tumor cells (8). Despite intensive efforts all approaches have not been overtly successful (9), suggesting that we need to better understand the underlying biology of tumor cells and their environment as they respond to immunotherapy. Recent studies have elucidated epigenetic pathway regulation of GBM tumor expansion (10), suggesting that combined epigenetic pathway inhibition with immunotherapy may be feasible. In this review, we discuss current GBM clinical trials and how immune system interactions with epigenetic pathways and signaling nodes can be delineated to uncover potential combination therapies for this incurable disease.

/pdf/immunotherapy-and-epigenetic-pathway-modulation-in-57c2giiqi4.pdf

Immunotherapy and Epigenetic Pathway Modulation in Glioblastoma Multiforme.

The invention includes biguanidine derivatives of therapeutic agents of Formula IA or Formula IB including pharmaceutically acceptable, prodrugs, metabolites and isomers thereof. The invention also provides methods of preparation and use of these compounds for treating and/or preventing a wide variety of disease conditions and disorders. The invention also includes pharmaceutical compositions, preparation of prodrugs, and mutual prodrugs comprised of the constituent compounds of Formula IA, Formula IB Formula IC and Formula ID.

Biguanidine derivatives of therapeutic agents and methods of preparation and use thereof

The present invention provides novel uses of a biguanide derivative for preventing or treating glioblastoma. The compound of Formula 1 and its pharmaceutically acceptable salts can be used for preventing and treating glioblastoma. Further, the combined treatment of the compound of Formula 1 and temozolomide can provide superior effects compared to the administration of the compound of Formula 1 alone or temozolomide alone.

Pharmaceutical composition comprising a biguanide derivative as an active ingredient for preventing or treating glioblastoma

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a poor prognosis despite multimodal interventions. For brain tumors, immunotherapy has not yet fully proved their potential. The central nervous system has historically been regarded as an immune privileged organ, throwing doubt on application of immunotherapy to GBM. However, growing evidences suggest that immune cells can traverse the blood-brain barrier and affect immune responses in the brain. Although immunotherapy by programmed cell death protein 1 (PD-1) blockade has dramatically improved the survival rate of some types of cancer patients, its application to GBM still needs further investigation. To improve efficacy of immunotherapy, there have been many attempts for finding effective combination partner in several types of tumors. We hypothesized that TMZ could work synergistically with PD-1 blockade to generate a robust antitumor response against GBM. Here, we evaluated therapeutic responses of PD-1 blockade and its combination with temozolomide (TMZ) in mouse GBM model. PD-1 blockade remarkably showed long-term antitumor effects, and combined use of TMZ further improved survival rate. However, distinct working mechanisms operated in these two therapeutic strategies. Anti-PD-1 monotherapy significantly augmented the number of tumor-infiltrating lymphocytes and protected them from exhaustion. In comparison, TMZ combination abrogated these effects, suggesting that superior therapeutic efficacy did not originated from increased immune responses. Microarray experiments revealed that anti-PD-1 and combination groups differentially converted transcriptional programs, particularly emphasized by mutually exclusive functional annotation by ImmuneSigDB gene sets. Moreover, tumor rechallenge study showed that immunologic memory was generated only in the anti-PD-1 monotherapy group. Although TMZ did not facilitate anti-PD-1-mediated immune response or memory function, these data suggest that combined treatment of anti-PD-1 and TMZ exert robust antitumor efficacy with therapeutic benefits in GBM. In addition, our data suggest possibility of immunotherapy to be added in standard treatment modalities of GBM.

/pdf/immu-16-effect-of-anti-pd-1-therapy-combination-on-2jo72loqcw.pdf

Immu-16. effect of anti-pd-1 therapy combination on temozolomide in mouse glioblastoma.

https://pubs.rsna.org/doi/pdf/10.1148/radiol.2016151913

incremental Prognostic Value of aDc histogram analysis over MgMT Promoter Methylation s tatus in Patients with

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Pharmaceutical composition comprising a biguanide derivative as an active ingredient for preventing or treating glioblastoma

Immu-16. effect of anti-pd-1 therapy combination on temozolomide in mouse glioblastoma.

incremental Prognostic Value of aDc histogram analysis over MgMT Promoter Methylation s tatus in Patients with