Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models

Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 is a selective CYP450 inhibitor, which has been shown to inhibit angiogenesis and tumor growth. Therefore, to explore novel treatments, we have generated an improved intravenous (IV) formulation of HET0016 with HPßCD and tested in animal models of human and syngeneic GBM. Administration of a single IV dose resulted in 7-fold higher levels of HET0016 in plasma and 3.6-fold higher levels in tumor at 60 min than that in IP route. IV treatment with HPßCD-HET0016 decreased tumor growth, and altered vascular kinetics in early and late treatment groups (p \u3c 0.05). Similar growth inhibition was observed in syngeneic GL261 GBM (p \u3c 0.05). Survival studies using patient derived xenografts of GBM811, showed prolonged survival to 26 weeks in animals treated with focal radiation, in combination with HET0016 and TMZ (p \u3c 0.05). We observed reduced expression of markers of cell proliferation (Ki-67), decreased neovascularization (laminin and αSMA), in addition to inflammation and angiogenesis markers in the treatment group (p \u3c 0.05). Our results indicate that HPßCD-HET0016 is effective in inhibiting tumor growth through decreasing proliferation, and neovascularization. Furthermore, HPßCD-HET0016 significantly prolonged survival in PDX GBM811 model

Arachidonic Acid Metabolite as a Novel Therapeutic Target in Breast Cancer Metastasis

Metastatic breast cancer (BC) (also referred to as stage IV) spreads beyond the breast to the bones, lungs, liver, or brain and is a major contributor to the deaths of cancer patients. Interestingly, metastasis is a result of stroma-coordinated hallmarks such as invasion and migration of the tumor cells from the primary niche, regrowth of the invading tumor cells in the distant organs, proliferation, vascularization, and immune suppression. Targeted therapies, when used as monotherapies or combination therapies, have shown limited success in decreasing the established metastatic growth and improving survival. Thus, novel therapeutic targets are warranted to improve the metastasis outcomes. We have been actively investigating the cytochrome P450 4 (CYP4) family of enzymes that can biosynthesize 20-hydroxyeicosatetraenoic acid (20-HETE), an important signaling eicosanoid involved in the regulation of vascular tone and angiogenesis. We have shown that 20-HETE can activate several intracellular protein kinases, pro-inflammatory mediators, and chemokines in cancer. This review article is focused on understanding the role of the arachidonic acid metabolic pathway in BC metastasis with an emphasis on 20-HETE as a novel therapeutic target to decrease BC metastasis. We have discussed all the significant investigational mechanisms and put forward studies showing how 20-HETE can promote angiogenesis and metastasis, and how its inhibition could affect the metastatic niches. Potential adjuvant therapies targeting the tumor microenvironment showing anti-tumor properties against BC and its lung metastasis are discussed at the end. This review will highlight the importance of exploring tumor-inherent and stromal-inherent metabolic pathways in the development of novel therapeutics for treating BC metastasis

1 Examining the immune tumor microenvironment of endometrial cancer patients treated with pembrolizumab plus lenvatinib

Objectives: Our aim is to examine the immune microenvironment of endometrial cancer (EMCA) patients treated with pembrolizumab plus lenvatinib (P+L) that could contribute to increased time on treatment. This may help inform patient selection and identify new therapeutic targets among aggressive endometrial cancer subtypes. Methods: 229 endometrial cancer patients were analyzed using Next-Gen sequencing of the DNA (NextSeq, 592 genes or NovaSeq, WES) and RNA (NovaSeq, WTS) (Caris Life Sciences, Phoenix, AZ. Time on treatment (TOT) was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts as the time of first to last treatment of P+L. Responders (R) and non-responders (NR) were defined by treatment for > or <6 months, respectively. Relative abundance of immune-cell infiltrates was calculated by Quantiseq. T-cell inflamed score was calculated from a 160 gene expression signature, and the interferon (IFN) score was calculated from an 18-gene signature. Statistical significance was calculated using Mann-Whitney U test. Results: The median TOT of P+L was 4.97 months for all EMCA patients treated with P+L (n=229). The mTOT for endometrioid EMCA patients (n=93) was 5.96 months compared to 3.49 mToT for serous EMCA (n=76) (HR: 0.543, 95% CI (0.395-0.746), p-value <0.001). Overall, all EMCA responders had higher median HLA class 2 gene expression (HLA-DQB2, 2.31-fold; HLA-DPB1, 1.42-fold; HLA-DQA1, 1.66-fold; HLA-DRB1, 1.40-fold; HLA-DPA1, 1.33-fold) and CD8+ T-cells (0.42% vs 0.06%) (p<0.05). Of endometrioid EMCA patients, responders had increased median HLA class 2 gene expression (HLA-DPB1, 2.059-fold; HLA-DQA1, 2.580-fold; HLA-DRB1, 1.568-fold; HLA-DPA1, 1.765-fold) (all p<0.05), but no significant differences in immune cell infiltrates or immune signatures. In serous EMCA, responders also had higher median HLA class 2 gene expression (HLA-DQB2, 4.30-fold; HLA-DPB1, 1.60-fold; HLA-DOB, 2.10-fold), CD8+ T cells, (1.41% vs 0.16%), IFN score (–0.0383 vs –0.265) and T-cell inflamed score (48 vs –67) (all p<0.05). Conclusions: Components of cytotoxic T-cell response in the TME including elevated IFN-γ and T-cell inflamed scores in conjunction with high expression of HLA class II was associated with longer time on treatment with P+L among serous endometrial cancers

Major Challenges and Potential Microenvironment-Targeted Therapies in Glioblastoma

Glioblastoma (GBM) is considered one of the most malignant, genetically heterogeneous, and therapy-resistant solid tumor. Therapeutic options are limited in GBM and involve surgical resection followed by chemotherapy and/or radiotherapy. Adjuvant therapies, including antiangiogenic treatments (AATs) targeting the VEGF–VEGFR pathway, have witnessed enhanced infiltration of bone marrow-derived myeloid cells, causing therapy resistance and tumor relapse in clinics and in preclinical models of GBM. This review article is focused on gathering previous clinical and preclinical reports featuring major challenges and lessons in GBM. Potential combination therapies targeting the tumor microenvironment (TME) to overcome the myeloid cell-mediated resistance problem in GBM are discussed. Future directions are focused on the use of TME-directed therapies in combination with standard therapy in clinical trials, and the exploration of novel therapies and GBM models for preclinical studies. We believe this review will guide the future of GBM research and therapy

Changes in the tumor microenvironment and outcome for TME-targeting therapy in glioblastoma: A pilot study.

Glioblastoma (GBM) is a hypervascular and aggressive primary malignant tumor of the central nervous system. Recent investigations showed that traditional therapies along with antiangiogenic therapies failed due to the development of post-therapy resistance and recurrence. Previous investigations showed that there were changes in the cellular and metabolic compositions in the tumor microenvironment (TME). It can be said that tumor cell-directed therapies are ineffective and rethinking is needed how to treat GBM. It is hypothesized that the composition of TME-associated cells will be different based on the therapy and therapeutic agents, and TME-targeting therapy will be better to decrease recurrence and improve survival. Therefore, the purpose of this study is to determine the changes in the TME in respect of T-cell population, M1 and M2 macrophage polarization status, and MDSC population following different treatments in a syngeneic model of GBM. In addition to these parameters, tumor growth and survival were also studied following different treatments. The results showed that changes in the TME-associated cells were dependent on the therapeutic agents, and the TME-targeting therapy improved the survival of the GBM bearing animals. The current GBM therapies should be revisited to add agents to prevent the accumulation of bone marrow-derived cells in the TME or to prevent the effect of immune-suppressive myeloid cells in causing alternative neovascularization, the revival of glioma stem cells, and recurrence. Instead of concurrent therapy, a sequential strategy would be better to target TME-associated cells

Nf1 deletion results in depletion of the Lhx6 transcription factor and a specific loss of parvalbumin+ cortical interneurons

Neurofibromatosis 1 (NF1) is caused by mutations in the NF1 gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse Nf1 from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Nf1 loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss of Nf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss of Nf1 results in a dose-dependent decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone

Tsc1 represses parvalbumin expression and fast-spiking properties in somatostatin lineage cortical interneurons.

Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. However, mechanisms regulating their diversity remain poorly understood. Here, we show that conditional loss of the Tuberous Sclerosis Complex (TSC) gene, Tsc1, which inhibits the mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs. Milder intermediate phenotypes also occur when only one allele of Tsc1 is deleted. Notably, treatment of adult mice with rapamycin, which inhibits MTOR, reverses the phenotypes. These data reveal novel functions of MTOR signaling in regulating PV expression and FS properties, which may contribute to TSC neuropsychiatric symptoms. Moreover, they suggest that CINs can exhibit properties intermediate between those classically associated with PV+ or SST+ CINs, which may be dynamically regulated by the MTOR signaling