Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo

Boyd, Nathaniel H.; Walker, Kiera; Fried, Joshua; Hackney, James R.; McDonald, Paul C.; Benavides, Gloria A.; Spina, Raffaella; Audia, Alessandra; Scott, Sarah; Libby, Catherine; Tran, Anh; Bevensee, Mark O.; Griguer, Corinne E.; Nozell, Susan E.; Gillespie, G. Yancey; Nabors, Burt; Bhat, Krishna; Bar, Eli E.; Darley‐Usmar, Victor; Xu, Bo; Gordon, Emily R.; Cooper, Sara J.; Dedhar, Shoukat; Hjelmeland, Anita B.

doi:10.1172/jci.insight.92928

Cited by 103 publications

(99 citation statements)

References 59 publications

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“…CAIX plays a role in tumor growth and survival, invasion and metastasis, and mobilization of immune-suppressive myeloidderived suppressor cells, making it an attractive therapeutic target (21). Therapeutically targeting CAIX in hypoxic solid tumors with the specific small-molecule SLC-0111 inhibits tumor growth and metastases in preclinical models of breast and brain cancer (22)(23)(24). SLC-0111 has now entered clinical evaluation and has, thus far, been found to be well tolerated (25).…”

Section: Introductionmentioning

confidence: 99%

Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically

Chafe¹,

McDonald²,

Saberi³

et al. 2019

Cancer Immunology Research

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119

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Treatment strategies involving immune-checkpoint blockade (ICB) have significantly improved survival for a subset of patients across a broad spectrum of advanced solid cancers. Despite this, considerable room for improving response rates remains. The tumor microenvironment (TME) is a hurdle to immune function, as the altered metabolism-related acidic microenvironment of solid tumors decreases immune activity. Here, we determined that expression of the hypoxia-induced, cell-surface pH regulatory enzyme carbonic anhydrase IX (CAIX) is associated with worse overall survival in a cohort of 449 patients with melanoma. We found that targeting CAIX with the small-molecule SLC-0111 reduced glycolytic metabolism of tumor cells and extracellular acidification, resulting in increased immune cell killing. SLC-0111 treatment in combination with immune-checkpoint inhibitors led to the sensitization of tumors to ICB, which led to an enhanced Th1 response, decreased tumor growth, and reduced metastasis. We identified that increased expression of CA9 is associated with a reduced Th1 response in metastatic melanoma and basal-like breast cancer TCGA cohorts. These data suggest that targeting CAIX in the TME in combination with ICB is a potential therapeutic strategy for enhancing response and survival in patients with hypoxic solid malignancies.

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Section: Introductionmentioning

confidence: 99%

Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically

Chafe¹,

McDonald²,

Saberi³

et al. 2019

Cancer Immunology Research

Self Cite

119

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“…Our analyses show that a large proportion of the genes that are associated with FLC-specific enhancers function in drug resistance, including LINC00473 (Han et al, 2018;Wang et al, 2018), VCAN (Li et al, 2017), and CA12 (Boyd et al, 2017;Doyen et al, 2013;Kopecka et al, 2016;Yoo et al, 2010). This suggests that high expression of these genes may be responsible for the strong drug resistance phenotype observed in FLC.…”

Section: Discussionmentioning

confidence: 61%

“…LINC00473 is known to be overexpressed in FLC (Dinh et al, 2017) and other cancers (Chen et al, 2016(Chen et al, , 2018Shi et al, 2017), and promotes chemotherapeutic resistance in colon cancer and head and neck squamous cell carcinoma (Han et al, 2018). CA12 has been linked to drug resistance in multiple cancer types (Boyd et al, 2017;Doyen et al, 2013;Kopecka et al, 2016) and we have previously demonstrated that it is overexpressed in FLC (Dinh et al, 2017). Other genes, including SLC16A14 and FAM19A5, are relatively understudied and merit deeper investigation.…”

Section: Discussionmentioning

confidence: 75%

“…Bars outlined in black designate genes that have sufficient enhancer signal in individual unique enhancers to meet the threshold originally determined for FLC-specific enhancer hotspots. (Dinh et al, 2017) and because CA12 is a prominent mediator of drug resistance in other cancer types (Boyd et al, 2017;Doyen et al, 2013;Kopecka et al, 2016;Yoo et al, 2010); and HSPA1B because it encodes a member of the heat shock protein 70 (HSP70) family, which has been shown to interact with the DNAJB1-PRKACA fusion found in FLC . We also selected one gene that only appears in the FLC-specific enhancer hotspot analysis (RPS6KA2) and another from the gene-enhancer correlation (FZD10) analysis for further investigation (Fig.…”

Section: High-confidence Candidate Oncogenes In Flcmentioning

confidence: 99%

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Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal molecular mechanisms of oncogenesis and intrinsic drug resistance

Dinh

Sritharan

Smith

et al. 2020

Preprint

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Fibrolamellar carcinoma (FLC) is a rare, therapeutically intractable liver cancer that disproportionately affects youth. Although FLC tumors exhibit a distinct gene expression profile, the causative transcriptional mechanisms remain unclear. Here we used chromatin run-on sequencing to discover approximately 7,000 enhancers and 141 enhancer hotspots activated in FLC relative to non-malignant liver. Detailed bioinformatic analyses revealed aberrant ERK/MEK signaling and candidate master transcriptional regulators. We also defined the genes most strongly associated with aberrant FLC enhancer activity, including CA12 and SLC16A14. Treatment of FLC cell models with inhibitors of CA12 or SLC16A14 independently reduced cell viability and/or significantly enhanced the effect of MEK inhibitor cobimetinib. These findings highlight new molecular targets for drug development as well as novel drug combination approaches.

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“…Its prognosis remains poor, even with the current standard of care, i.e., a combination of surgery, radiotherapy, and chemotherapy 3,4) . The disease course of GBM is typically rapid, and it has a 5-year survival rate of only 10% and a median survival time of 15 months following intensive treatment [5][6][7][8] . Therefore, there remains a strong need for novel therapeutic strategies to treat GBM.…”

Section: Introductionmentioning

confidence: 99%

Identification of cephalomannine as a drug candidate for glioblastoma via high-throughput drug screening

Qiao

Kondo

2018

J. Electrophor

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Glioblastoma (GBM) is the most common malignant primary tumor of the central nervous system in adults. Despite advances in GBM treatment, the prognosis of patients with GBM remains poor and novel drugs are urgently required. In this study, we aimed to identify novel drugs for GBM treatment by using a drug screening approach. To this end, we performed high-throughput screening with 118 drugs, including Food and Drug Administration (FDA)-approved anticancer drugs. We found high inhibition rates (more than 90%) for doxorubicin, bortezomib, and cephalomannine in 6 GBM cell lines. Furthermore, we determined the half-maximal inhibitory concentration (IC 50 ) of cephalomannine and found that the drug has a high potential for anti-GBM activity. Moreover, we noted that cephalomannine inhibited cell proliferation by inducing autophagy. Thus, our results indicate that cephalomannine may be an effective drug candidate for GBM treatment.

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Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo

Cited by 103 publications

References 59 publications

Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically

Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically

Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal molecular mechanisms of oncogenesis and intrinsic drug resistance

Identification of cephalomannine as a drug candidate for glioblastoma via high-throughput drug screening

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