Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo
Nathaniel BoydKiera WalkerJoshua FriedJames R. HackneyPaul C. McDonaldGloria A. BenavidesRaffaella SpinaAlessandra AudiaSarah ScottCatherine LibbyAnh TranMark O. BevenseeCorinne E. GriguerSusan E. NozellG. Yancey GillespieBurt NaborsKrishna BhatEli E. BarVictor Darley‐UsmarBo XuEmily R. GordonSara J. CooperShoukat DedharAnita B. Hjelmeland
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Abstract:
Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor-initiating cell hypothesis. Standard of care for glioblastoma (GBM) includes temozolomide chemotherapy, which is not curative, due, in part, to residual therapy-resistant brain tumor-initiating cells (BTICs). Temozolomide efficacy may be increased by targeting carbonic anhydrase 9 (CA9), a hypoxia-responsive gene important for maintaining the altered pH gradient of tumor cells. Using patient-derived GBM xenograft cells, we explored whether CA9 and CA12 inhibitor SLC-0111 could decrease GBM growth in combination with temozolomide or influence percentages of BTICs after chemotherapy. In multiple GBMs, SLC-0111 used concurrently with temozolomide reduced cell growth and induced cell cycle arrest via DNA damage in vitro. In addition, this treatment shifted tumor metabolism to a suppressed bioenergetic state in vivo. SLC-0111 also inhibited the enrichment of BTICs after temozolomide treatment determined via CD133 expression and neurosphere formation capacity. GBM xenografts treated with SLC-0111 in combination with temozolomide regressed significantly, and this effect was greater than that of temozolomide or SLC-0111 alone. We determined that SLC-0111 improves the efficacy of temozolomide to extend survival of GBM-bearing mice and should be explored as a treatment strategy in combination with current standard of care.Keywords:
Temozolomide
Dacarbazine
Glioblastoma multiforme (GBM) is one of the most aggressive primary tumors of the central nervous system. It is associated with a very poor prognosis, with up to half of patients failing to survive the first year after diagnosis. It develops from glial tissue and belongs to the adult-type diffuse glioma group according to the WHO classification of 2021. Therapy for patients with GBM is currently based on surgical resection, radiation therapy, and chemotherapy, but despite many efforts, there has been minimal progress in tumor management. The most important chemotherapeutic agent in the treatment of this tumor is temozolomide (TMZ), a dacarbazine derivative that presents alkylating activity. It is usually administered to patients concurrently with radiation therapy after surgical resection of the tumor, which is defined as the Stupp protocol. Temozolomide demonstrates relatively good efficacy in therapy, but it could also present with several side effects. The resistance of GBM to the drug is currently the subject of work by specialists in the field of oncology, and its use in various regimens and patient groups may bring therapeutic benefits in the future. The aim of this review paper is to summarize the relevance of TMZ in the treatment of GBM based on recent reports.
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Purpose: Temozolomide is an imidazotetrazine with a mechanism of action similar to dacarbazine and equivalent activity in melanoma. It is well tolerated and is a candidate for combination chemotherapy and schedule manipulation. In this study, we combined temozolomide with interferon alfa-2b and, separately, with thalidomide, and we administered temozolomide alone in a compressed schedule. The objectives of this randomized phase II, two-center study were to determine response rates, overall survival, and tolerability of the regimens in patients with advanced metastatic melanoma. Patients and Methods: One hundred eighty-one patients with metastatic melanoma were randomly assigned to receive up to six 4-weekly cycles consisting of temozolomide 200 mg/m 2 every 8 hours for five doses, or temozolomide 200 mg/m 2 daily for days 1 to 5 plus interferon alfa-2b 5 MU (million International Units) subcutaneously three times a week, or temozolomide 150 mg/m 2 (increased after one cycle to 200 mg/m 2 ) daily on days 1 to 5 plus thalidomide 100 mg daily days 1 to 28. Results: The treatment arms were well balanced for known prognostic factors. Median survival was 5.3 months for 8-hourly temozolomide, 7.7 months for temozolomide/interferon, and 7.3 months for temozolomide/thalidomide; and 1-year survivals were 18%, 26%, and 24%, respectively. Response or disease stabilization occurred in 20% of patients (95% confidence interval [CI], 10% to 33%) given 8-hourly temozolomide, 21% (95% CI, 12% to 33%) given temozolomide/interferon, and 25% (95% CI, 15% to 38%) given temozolomide/thalidomide. Grade 3 or 4 nonhematologic toxicities were similar in each arm except for infection, which was more frequent with 8-hourly temozolomide. There were fewer instances of grade 3 or 4 myelotoxicity with temozolomide/thalidomide. Conclusion: Of the three regimens tested, the combination of temozolomide and thalidomide seems the most promising for future study.
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Over the past 30 years, there has been no significant improvement in treatment outcomes for patients with advanced stage IV metastatic melanoma, and prognosis remains poor. Melanoma is known to be responsive to immunomodulatory agents, to be a highly vascular tumor, and to be fairly resistant to standard cytotoxic chemotherapy. Ongoing research is attempting to find novel combinations that may have therapeutic synergy. Alternative dose-dense schedules of temozolomide appear promising and are being actively investigated, based on their potential to overcome chemoresistance to alkylating agents and the proven activity of temozolomide in the brain. Outcomes of studies investigating single-agent temozolomide suggest that it has activity similar to single-agent dacarbazine. Other studies combining temozolomide with either interferon-alfa or thalidomide suggest that the addition of these immunomodulatory agents to temozolomide improves response rates and may improve overall survival. The best results have been achieved with the extended, daily, dose-dense temozolomide regimen. Further research is needed to determine the optimal temozolomide regimen and best combination approach for the treatment of advanced metastatic melanoma.
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Over the past 30 years, there has been no significant improvement in treatment outcomes for patients with advanced stage IV metastatic melanoma, and prognosis remains poor. Melanoma is known to be responsive to immunomodulatory agents, to be a highly vascular tumor, and to be fairly resistant to standard cytotoxic chemotherapy. Ongoing research is attempting to find novel combinations that may have therapeutic synergy. Alternative dosedense schedules of temozolomide appear promising and are being actively investigated, based on their potential to overcome chemoresistance to alkylating agents and the proven activity of temozolomide in the brain. Outcomes of studies investigating single-agent temozolomide suggest that it has activity similar to single-agent dacarbazine. Other studies combining temozolomide with either interferon- alfa or thalidomide suggest that the addition of these immunomodulatory agents to temozolomide improves response rates and may improve overall survival. The best results have been achieved with the extended, daily, dosedense temozolomide regimen. Further research is needed to determine the optimal temozolomide regimen and best combination approach
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Temozolomide is an imidazotetrazine with a mechanism of action and efficacy similar to dacarbazine (DTIC). However, it differs from DTIC in that it can be taken orally, degrades spontaneously to an active metabolite and penetrates the blood–brain barrier. It is well tolerated, making it a suitable candidate for combination chemotherapy. Trials to date have focussed on its activity in advanced metastatic melanoma and high-grade malignant glioma. Investigations into other indications, in particular solid tumors with central nervous system metastases, are ongoing. Studies of new drug schedules and of drugs to ameliorate temozolomide resistance offer the prospect of increased efficacy.
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Abstract Background. This systematic review examines the role of temozolomide in patients with metastatic melanoma. Outcomes of interest include response rate, progression-free survival, overall survival, quality of life, and adverse effects. Methods. The MEDLINE, EMBASE, and Cochrane Library databases were searched from 1980 through to 2005 using variations on the search terms: melanoma, clinical trial, random, temozolomide, temodal, and temodar. The American Society of Clinical Oncology Annual Meeting proceedings were searched from 1996 to 2005. Relevant articles and abstracts were selected and reviewed by two reviewers, and the reference lists from these sources were searched for additional trials. Results. Two randomized phase III trials and three randomized phase II trials were located. In addition, 21 phase I or II trials investigating single-agent temozolomide, temozolomide plus interferon-α, and temozolomide plus thalidomide were reviewed. A direct comparison of temozolomide and dacarbazine demonstrated equal efficacy for response rates and overall survival; however, no significant difference was reported. A second phase III study comparing single-agent temozolomide with temozolomide combined with interferon-α indicated a significantly higher response rate for the combination treatment arm, but no difference in overall survival was noted. Further phase III studies are required to confirm whether there is a benefit associated with the combination of temozolomide and interferon-α or thalidomide. Conclusion. Our review of the available literature suggests that temozolomide demonstrates comparable activity to the current standard treatment, dacarbazine, with the additional benefit of being a convenient oral treatment that penetrates the blood–brain barrier.
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No standard treatment of recurrent malignant glioma is established. Moreover, it is unclear if rechallenge with Temozolomide is effective. We present here feasibility and first treatment results of a dose dense, individually dose adapted 21-day regimen with Temozolomide for recurrent malignant gliomas.
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Temozolomide (Temodar) has demonstrated clinical activity against melanoma equivalent to that of intravenous dacarbazine (DTIC). Phase I clinical studies have shown that low dose chronic administration of temozolomide permits the delivery of higher dose intensities than a 5 day dose schedule. Temozolomide is hydrolysed to its active metabolite monomethyltriazenoimidazole carboxamide (MTIC) upon absorption from the gastrointestinal tract, while DTIC is inactive until it is metabolized in the liver to MTIC. In view of this, a higher concentration of MTIC will pass through the liver during the first pass when its source is temozolomide rather than DTIC. To determine if these characteristics of temozolomide will translate into a higher response rate than that achieved with DTIC, we conducted a phase II clinical trial of temozolomide in patients with uveal melanoma metastatic to the liver. Temozolomide was administered orally at a starting dose of 75 mg/m2 per day for 21 days every 4 weeks. Fourteen patients were enrolled in the trial. No complete or partial responses were observed. Stabilization of disease was achieved in two patients. The treatments were well tolerated. We conclude that, like DTIC, temozolomide at the dose and schedule studied in this trial is not effective for the control of metastatic melanoma of uveal origin.
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Purpose of review The discovery of temozolomide in the 1980s was expected to be an important advance in improving survival for patients with malignant brain tumors. Numerous clinical studies have demonstrated the activity of temozolomide against recurrent or refractory gliomas and noncentral nervous system malignancies. In the last 2 years, studies have focused on exploring strategies to optimize the efficacy of temozolomide, including evaluating different temozolomide dosing schedules and combining temozolomide with other antineoplastic agents, radiation therapy, or drug resistance-modifying agents. Recent findings A critical review of these studies suggests that temozolomide, as currently used, has limited efficacy in treating refractory malignant infiltrative brain tumors, and survival benefit is, at best, a few weeks longer than that with procarbazine. There is enthusiasm about the activity of temozolomide in the treatment of recurrent low-grade gliomas and advanced malignant melanomas. Temozolomide has activity and a favorable safety profile in all dosing schedules tested. Nevertheless, the trials evaluating the efficacy of temozolomide suffer from being uncontrolled, with short follow-up periods. Summary Despite the advantages of a favorable safety profile and oral administration, temozolomide has yet to realize its initial promise and full potential. Studies of temozolomide combined with novel drug resistance-modifying agents will likely improve disease control while minimizing toxicities, leading to improved survival benefit. Larger, randomized trials comparing temozolomide with standard therapy are needed to confirm the suggested benefit from temozolomide in malignant brain tumors. Temozolomide will continue to be attractive as an agent in the treatment of brain tumors because of its desirable features and safety.
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