HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer

Fukumoto, Takeshi; Fatkhutdinov, Nail; Zundell, Joseph A.; Tcyganov, Evgenii N.; Nacarelli, Timothy; Karakashev, Sergey; Wu, Shuai; Liu, Qin; Gabrilovich, Dmitry I.; Zhang, Rugang

doi:10.1158/0008-5472.can-19-1302

Cited by 91 publications

(56 citation statements)

References 26 publications

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“…123 This is consistent with the demonstration that HDAC6 inhibition can synergize with anti-PD-L1 therapy in a mouse model, raising the possibility that this combination may represent a novel therapeutic strategy. 124 In early work, prolyl hydroxylase domain-containing protein 2 (PHD2), encoded by EGLN1, has been identified as a potential hypoxia-inducible factor 1α (HIF1A)-dependent therapeutic target in clear cell carcinoma; 125 and screening of ARID1A-deficient cells has suggested that gemcitabine may be an effective therapeutic option in ARID1A-deficient tumors. 126 Post-Treatment Surveillance Current NCCN guidelines do not recommend clear cell carcinomaspecific post-treatment surveillance; 87 patients are followed up in the same way as patients with other histological tumor types.…”

Section: Radiotherapymentioning

confidence: 99%

Clear cell carcinoma of the ovary: a clinical and molecular perspective

Iida

Okamoto

Hollis

et al. 2020

Int J Gynecol Cancer

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Clear cell carcinoma of the ovary has distinct biology and clinical behavior. There are significant geographical and racial differences in the incidence of clear cell carcinoma compared with other epithelial ovarian tumors. Patients with clear cell carcinoma are younger, tend to present at an early stage, and their tumors are commonly associated with endometriosis, which is widely accepted as a direct precursor of clear cell carcinoma and has been identified pathologically in approximately 50% of clear cell carcinoma cases. The most frequent and important specific gene alterations in clear cell carcinoma are mutations of AT-rich interaction domain 1A (ARID1A) (~50% of cases) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (~50% cases). More broadly, subgroups of clear cell carcinoma have been identified based on C-APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and C-AGE (age-related) mutational signatures. Gene expression profiling shows upregulation of hepatocyte nuclear factor 1-beta (HNF1β) and oxidative stress-related genes, and has identified epithelial-like and mesenchymal-like tumor subgroups. Although the benefit of platinum-based chemotherapy is not clearly defined it remains the mainstay of first-line therapy. Patients with early-stage disease have a favorable clinical outcome but the prognosis of patients with advanced-stage or recurrent disease is poor. Alternative treatment strategies are required to improve patient outcome and the development of targeted therapies based on molecular characteristics is a promising approach. Improved specificity of the histological definition of this tumor type is helping these efforts but, due to the rarity of clear cell carcinoma, international collaboration will be essential to design appropriately powered, large-scale clinical trials.

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Section: Radiotherapymentioning

confidence: 99%

Clear cell carcinoma of the ovary: a clinical and molecular perspective

Iida

Okamoto

Hollis

et al. 2020

Int J Gynecol Cancer

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“…Fukumoto et al showed that inhibition of HDAC6 synergizes with PD-L1 inhibitors in ARID1A-inactivated OC. These findings suggest a rationale for combining epigenetic modulators and PD-L1 inhibitors against OC [64].…”

Section: Monotherapy or Combination Therapy With Pd-l1 Inhibitors Inmentioning

confidence: 83%

The Latest Findings of PD-1/PD-L1 Inhibitor Application in Gynecologic Cancers

Kooshkaki

Derakhshani

Safarpour

et al. 2020

IJMS

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Gynecologic cancers account for approximately 11% of the newly diagnosed cancers in women in the United States and for 18% globally. The presence of tumor-infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICIs), including anti programmed cell death protein-1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), and anticytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), which have been approved for treating different types of malignancies. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host–tumor interaction. There are several the US food and drug administration (FDA)-approved ICIs targeting PD-1, including pembrolizumab and nivolumab, as well as those targeting PD-L1, including avelumab, atezolizumab, and durvalumab for melanoma, renal cell cancer, colorectal cancer, head and neck cancer, cervix cancer, urothelial cancer, and lung cancer. Current pre-clinical and clinical studies assessing PD-1/PD-L1 inhibitors in several gynecologic cancers have reported significant antitumor activity. In this review, we investigate pre-clinical and clinical studies that describe the safety and efficacy of anti-PD-1/PD-L1 antibodies, with a particular focus on ongoing clinical trials, analyzing the oncological outcome and adverse effects of ICIs in gynecologic cancers.

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“…Inhibition of HDACs lead to increased histone acetylation, resulting in increased gene expression [75]. Recently, both the HDAC inhibitor mocetinostat and inhibition of HDAC6 independently demonstrated a synergistic effect in combination with ICI, resulting in increased anti-tumor activity in NSCLC and ovarian cancer cell lines by increasing tumor antigen presentation and decreasing immune suppressive cell types [76,77]. Furthermore, in a phase I study, an adenovirus vector encoding the IL-12 gene was injected during surgery in the resection cavity walls of patients with recurrent high-grade glioma, followed by post-operative treatment with the oral activator for human IL-12, veledimex.…”

Section: Discussionmentioning

confidence: 99%

The Current Status of Immune Checkpoint Inhibitors in Neuro-Oncology: A Systematic Review

Brahm

Linde

Enting

et al. 2020

Cancers

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The introduction of immune checkpoint inhibitors (ICI), as a novel treatment modality, has transformed the field of oncology with unprecedented successes. However, the efficacy of ICI for patients with glioblastoma or brain metastases (BMs) from any tumor type is under debate. Therefore, we systematically reviewed current literature on the use of ICI in patients with glioblastoma and BMs. Prospective and retrospective studies evaluating the efficacy and survival outcomes of ICI in patients with glioblastoma or BMs, and published between 2006 and November 2019, were considered. A total of 88 studies were identified (n = 8 in glioblastoma and n = 80 in BMs). In glioblastoma, median progression-free (PFS) and overall survival (OS) of all studies were 2.1 and 7.3 months, respectively. In patients with BMs, intracranial responses have been reported in studies with melanoma and non-small-cell lung cancer (NSCLC). The median intracranial and total PFS in these studies were 2.7 and 3.0 months, respectively. The median OS in all studies for patients with brain BMs was 8.0 months. To date, ICI demonstrate limited efficacy in patients with glioblastoma or BMs. Future research should focus on increasing the local and systemic immunological responses in these patients.

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HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer

Cited by 91 publications

References 26 publications

Clear cell carcinoma of the ovary: a clinical and molecular perspective

Clear cell carcinoma of the ovary: a clinical and molecular perspective

The Latest Findings of PD-1/PD-L1 Inhibitor Application in Gynecologic Cancers

The Current Status of Immune Checkpoint Inhibitors in Neuro-Oncology: A Systematic Review

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