Reused Drugs to Fight Glioblastoma (part one)

Here we are at the seventh episode of the Ben Williams guide translation project on treatment options for Glioblastoma Multiforme. This is chapter 6 of the guide which however is very long and I will divide it into parts. In this first part we talk about Accutane, Celebrex, Chloroquine and Hydroxychloroquine, Hydroxychloroquine and Rapamycin, Cimetidine, Chloripramine and Dichloroacetate. There are several drugs, some of which have had interesting and sometimes decisive effects on some patients but gradually contradicting or disappointing in the different phases of the clinical trial. The idea I am getting is that the result in the specific case depends on the specific mutations of the single glioblastoma. The advice is still to use this information to discuss it with the medical team that is following you, which you can also indicate references to supporting scientific works.
The fund campaign launched on GoFund.me: Glioblastoma.it for CUSP-ND for Emanuele is proceeding. I ask you once again to share the link. In the next few days I will try to explain why a clinical trial costs so much. Enjoy the reading!

There are a large number of drugs which were initially developed for different purposes and which subsequent laboratory research has shown to have significant anti-cancer properties. Since these drugs have been used for years, they have well-defined toxicity profiles and are generally cheaper because they are not patented, they offer the possibility of increasing the benefits of the current standard treatment without significant additional toxicity. However, because their FDA approval is for different purposes, many if not most neuro-oncologists are reluctant to use their possible benefits as components of a treatment cocktail. Some of these drugs have been studied as single agents for the treatment of brain cancer and some have even been combined with the Stupp protocol which represents the standard of care.

Accutane (isotretinoin, 13-cis retinoic acid)

When Temodar was combined with accutane, a retinoid used to treat acne (also known as 13-cis-retinoic acid or isotretinoin), PFS-6 (for recurrent cancers improved from the historical value of 21 % of Temodar alone, to 32% (96).
However, a clinical study with newly diagnosed patients combining Temodar with accutane produced less impressive results (97). Fifty-five evaluable patients used both low-dose accutane and Temodar during radiotherapy, followed by Temodar and full-dose accutane, achieving a median survival time of only 57 weeks and a two-year survival of 20%, both below the survival rates from the large clinical trial with the same protocol using Temodar without accuting. A second retrospective clinical study in Canada (98) that combined accutane and Temodar with newly diagnosed patients produced a median survival of 15.1 months and a two-year survival of 26.7%, both comparable to when Temodar was used alone.
Although accutane does not appear to improve results when added to the standard Temodar protocol, it appears to have activity as a single agent. A phase II clinical trial that evaluated accutane for recurrent gliomas was conducted at the MD Anderson Brain Tumor Center (99). Median survival time was 58 weeks for patients with glioblastoma and 34 weeks for grade III gliomas. Aggregated on both tumor types (43 evaluable patients), 3 achieved partial tumor regression, 7 had minor regressions and 13 achieved tumor stabilization. A more complete report on the use of accutane on 86 patients with recurrent glioblastoma was less impressive (100). The median survival time from the start of treatment was 25 weeks and the PFS-6 was 19%. Accutane is now being used by MD Anderson as a “maintenance therapy” for patients after their initial treatment with radiation or traditional chemotherapy. It has also been used in Germany for patients who have had a complete response to other treatment modalities such as maintenance therapy (101). The main side effects were dry skin, chapped lips and headache, although occasional liver toxicity also occurred. Increases in blood lipid levels frequently occur, often requiring anti-cholesterol drugs such as Lipitor. Accutane can also produce severe birth defects when taken during pregnancy.
Although various data now suggest that accutane should not be combined with chemotherapy (for example, see the sub-chapter titled “A trial of 3 repositioned drugs plus Temodar), a series of studies with various types of cancer, including pancreatic , ovarian, colorectal and melanoma (although not yet on brain tumors), suggest that it can be very effective for patients who get a good response from their initial treatment protocol. This is particularly important for patients with GBM who have a clean MRI after surgery or after treatment with radiation and chemotherapy. An example of the ovarian cancer protocol involved 65 patients who received standard treatment of a taxane and a platinum-based drug (316). After one year of standard treatment, those who received a benefit switched to maintenance treatment using low-dose IL-2 subcutaneously plus 13 oral cRA at a dose of 0.5 mg / kg. This plan was continued for a year, after which the frequency of administration was gradually reduced. Patients who received this treatment plan had a median PFS of 23 months and a median survival of 53 months. At the same time, various measures of immune function (lymphocyte count, NK cell count) were substantially improved and there was a substantial reduction in the level of VEGF, which reflects a reduction in angiogenesis.

Celebrex (and other FANS)

Carcinogenesis of different types involves an inflammatory process. When you regularly take anti-inflammatory drugs such as aspirin or ibuprofen, the incidence of colon cancer is reduced by up to 50%. This substantial effectiveness motivated the study of the mechanisms of these benefits. One component of the inflammatory process is angiogenesis, which is now believed to be a key component of cancer growth. COX-2 enzymes play an important role in inflammation, so COX-2 inhibitors should reduce angiogenesis and inhibit tumor growth. Many nonsteroidal anti-inflammatory drugs (FANS) are known to be COX-2 inhibitors, but most (eg, Ibuprofen) also inhibit COX-1 enzymes, which are necessary for maintaining a healthy stomach lining, which is why which many NSAID users eventually develop an intolerance. Therefore, much attention has recently been given to new COX-2 inhibitors such as Celebrex that have been developed to avoid COX-1 inhibition for the treatment of arthritis. As inhibition of angiogenesis is one of the main new approaches to cancer treatment, some oncologists have begun to add Celebrex to their standard treatment protocols, based on laboratory results suggesting that COX-2 inhibitors inhibit growth. of the tumor. In recent meetings of the American Society for Clinical Oncology (ASCO), various clinical studies were reported that combined one or the other COX-2 inhibitor with conventional radiation, chemotherapy and new targeted treatments. The vast majority of these were phase 2 clinical trials using only a historical comparison with conventional treatment data to evaluate the added value of COX-2 inhibitors, and most of these concluded that there appears to be a significant benefit. Some larger randomized clinical trials (115, 116) showed substantial improvements in outcomes when Celebrex was added to standard chemotherapy protocols, while others failed to demonstrate a benefit.
Two clinical studies have been reported using Celebrex in the treatment of gliomas. In a clinical study conducted jointly by several New York hospitals, Temodar was combined with Celebrex (117). For the 46 patients in the study (37 with GBM), the PFS-6 was 35%. However, an unusual Temodar program was also used, so it’s unclear whether the results are due to the new Temodar program or the famousx combination. Celebrex was also combined with CPT-11 (118), a chemotherapeutic agent widely used for colon cancer, in patients with recurrent cancers and produced a PFS-6 value of 25%.

Chloroquine and hydroxychloroquine

In a series of studies carried on in Mexico City (23, 24, 25), patients received the traditional chemotherapy agent BCNU, with or without a daily dose of 150 mg of chloroquine (the equivalent of 250 mg of chloroquine phosphate) . The results say that patients who also received chloroquine had a median survival time of 25-33 months, while those who received BCNU alone had a median survival time of 11 months. Chloroquine at the dose used had no detectable toxicity. Since the cytotoxic mechanism of BCNU is similar to that of Temodar, it seems likely that chloroquine increases the efficacy of Temodar, although this has yet to be demonstrated. One of the numerous mechanisms by which chloroquine makes chemotherapy more effective is that it inhibits autophagy.
Unfortunately, a phase I / II multicenter study that tested adding hydroxychloroquine (which differs from chloroquine only in a single hydroxyl group) to standard radiochemotherapy for newly diagnosed glioblastoma showed no survival improvement over historical averages . In the Phase I safety and toxicity study, all 3 subjects treated with 800 mg / day hydroxychloroquine together with chemoradiotherapy experienced grade 3 or 4 neutropenia or thrombocytopenia and 600 mg / day was determined to be the maximum tolerated dose. . 76 patients were therefore treated at this dose in the phase 2 study. Inhibition of autophagy (the proposed mechanism of action) was not achieved at that dose and patient survival (median OS 15.6 months, survival at 2 years of 25%) was not improved compared to historical control groups.
Recent preclinical studies (305) have shown increased dependence on autophagy and sensitivity to chloroquine treatment in EGFR-over-expressing glioma cells, and any future trials with chloroquine for high-grade gliomas may benefit from a subgroup analysis based on the state of EGFR expression.

Hydroxychloroquine and Rapamycin (Sirolimus)

Both rapamycin (sirolimus), an inhibitor of the mTOR 1 complex, and hydroxychloroquine and chloroquine have been tested in early-stage clinical trials for glioblastoma. In 2016, a Taiwan-based group published a case series of three newly diagnosed glioblastoma patients who had been treated with a combination of rapamycin and hydroxychloroquine in addition to standard radiotherapy and temozolomide chemotherapy (356). Maintenance treatment with rapamycin and hydroxychloroquine was also administered after completion of adjuvant courses with temozolomide. The three patients were 62, 69 and 71 years old, making it likely that all three were wild-type (non-mutant) for IDH1.
Patient 1 (age 71) was treated with rapamycin plus hydroxychloroquine combination for an additional 18 months after completion of the chemotherapy courses. At the time of publication he had been free from recurrence for over 3 years. Similarly, the second patient (62 years old) was treated with rapamycin plus hydroxychloroquine for one year beyond completion of temozolomide chemotherapy. At the time of publication, he remained free of relapses, 30 months after the initial diagnosis. In the third case (69 years), grade 2 fatigue required reductions in the dose of rapamycin and hydroxychloroquine after 2 weeks, which was halved for the duration of the treatment. In this case, the treatment continued for only one month after the completion of chemotherapy. The relapse of the disease appeared 18 months after the initial surgery and the overall survival was 28 months.
Since two of the three patients were progression-free at the time of publication, the median PFS and survival for these patients had not yet been achieved but were at least 30 months (median follow-up). The shortest survival was in the patient whose therapy dose was reduced early. In contrast to these three patients, the entire group of 20 patients treated in this institution during the same period of time, mainly with radiation and only temozolomide after resection, had a median survival of only 13.7 months.
Unfortunately, no information was provided on the EGFR or PTEN status or other genetic alterations of these three patients, which could have provided clues to the biomarkers of response to rapamycin plus hydroxychloroquine treatment.

Cimetidine (Tagamet)

A strong candidate for a non-toxic addition to standard therapy is the old drug for stomach acid, cimetidine (trade name Tagamet). Although no clinical studies have yet been reported using it on brain tumor, impressive results have been reported on its use for colon cancer (132), the rationale is that it decreases cell migration (and thus tumor spread from the site). original) by affecting the critical genes that control cell adhesion. Support for its use comes from a recent experimental study in mice with glioblastoma that received temozolomide or temozolomide and cimetidine (133). Survival was substantially longer in the latter group. An important caveat about cimetidine is that it has the potential to interact with numerous other drugs in terms of metabolism in the liver, thereby affecting their actual concentration.

Clomipramine (chlorimipramine)

This older FDA approved drug was first used for the treatment of depression and also for the treatment of obsessive-compulsive neuroses. Its rationale as a treatment for gliomas is that it selectively depresses the mitochondrial function in glioma cells leaving normal cells unaffected, causing apoptosis (programmed cell death) of the former. At the ASCO meeting in 2005 (122) a clinical study was reported evaluating the outcome of its use with 27 patients with high-grade gliomas (the distribution of GBM with respect to grade 3 tumors was not reported in the abstract, nor the history clinic of patients). Chlorimipramine was added to their conventional treatment with doses from 25 mg per day increased to 150 mg per day. Median survival was 27 months; 20 of the 27 patients showed partial tumor regressions. This appears to be a promising new treatment, although further testing is clearly needed with a more detailed report of the results. An interesting aspect of chlorimipramine is that laboratory research has shown that it strongly potentiates the toxicity of gleevec to glioma cells (123).

Dichloroacetate (DCA)

This simple chemical compound has been used for the treatment of infantile lactic acidosis, a disorder of the mitochondria that control the energy production of a cell. Its use as a cancer treatment is based on the Warburg effect, the discovery that cancer cells are much more likely to use anaerobic metabolism, a very inefficient process, even in the presence of sufficient oxygen. DCA affects the mitochondrial membrane, thereby inhibiting anaerobic metabolism, which results in changes in the cellular microenvironment that can cause cancer cell death.
Because DCA is a simple chemical, it can be easily found, which has led to early experimental reports of its effectiveness against cancer motivating many cancer patients to take it without a prescription. Only recently has a report from a clinical study been published that appears to confirm previous laboratory results (124). A group in Alberta, Canada reported the results of five GBM patients, three with recurrent cancers and two newly diagnosed, who received DCA in combination with the standard temozolomide-based protocol. One of the three patients with recurrent cancer died after three months, due to massive edema due to his very large tumor present before the DCA treatment. All the others were still alive in the follow-up period 18 months after the start of therapy. Patients were treated with an initial oral dose of 12.5 mg / kg twice daily, increased to 25 mg / kg twice daily. The only apparent significant toxicity was peripheral neuropathy, which is however reversible. Doses of 6. 25 mg / kg twice daily produced no neuropathy. The authors noted that the serum concentration took 2-3 months to reach therapeutic concentrations. Remarkable is the recent laboratory discovery according to which the use of GBM cells implanted in a mouse xenograft model has shown a remarkable synergy between DCA and Avastin, a coherent logic on why this synergy is created (125).

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(23 Briceno, E., et al. Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine. Neurosurgical Focus, 2003, 14(2), e3.
(24) Sotelo, J., et al. Adding chloroquine to conventional treatment for glioblastoma multiforme: A randomized double-blind, placebo-controlled trial. Annals of Internal Medicine, 2006, Vol. 144 (5), 337-343.
(25) Briceno, E., et al. Institutional experience with chloroquine as an adjuvant to the therapy for glioblastoma multiforme. Surgical Neurology, 2007, 67(4), 388-391.
(96) Jaeckle, K. A., et al. Phase II evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive malignant glioma: A NABTC consortium study.
(97) Butowski, N., et al., A phase II study of concurrent temozolomide and cis-retinoic acid with radiation for adult patients with newly diagnosed supratentorial glioblastoma. Int. J. of Rad. Oncol., Biol., & Phys., 2005, 61(5), 1454-1459. 
(98) Pitz, M.W., Lipson, M., Hosseini, B., et al. Extended adjuvant temozolomide with cis-retinoic acid for adult glioblastoma. Current Oncology, 2012, 19(6), 308-14. 
(99) Yung, W. K. A. et al. Treatment of recurrent malignant gliomas with high-dose 13- cis-retinoic acid. Clinical Cancer Research, 1996 Vol. 2, pp. 1931-1935. 
(100) See, S. J. et al. 13-cis-Retinoic acid in the treatment of recurrent glioblastoma multiforme. Neuro-oncology, 2004, 6, 253-258. 
(101) Wismeth, C., et al. Maintenance therapy with 13-cis retinoic acid in high-grade glioma at complete response after first-line multimodal therapy–a phase II study. Journal of Neuro-oncology, 2004, 68, 79-86. 
(115) Mohammadianpanah, M., Razmjour-Ghalael, S., Shafizad, A., et al. Efficacy and safety of concurrent chemoradiation with weekly cisplatin +/- low-dose celecoxib in locally advanced undifferentiated nasopharyngeal carcinoma: a phase II-III clinical trial. Journal of Cancer Research & Therapy, 2011, 7(4), 442-47. 
(116) Debucquoy, A., Roels, S., Goethals, L., et al. Double blind randomized phase II study with radiation + 5-fluorouracil +/- celecoxib for resectable rectal cancer. Radiotherapy Oncology, 2009, 93(2), 272-78 
(117) Pannulo, S. et al. Phase I/II trial of twice-daily temozolomide and celecoxib for treatment of relapsed malignant glioma: Final Data. Proceedings of the American Society of Clinical Oncology, 2006, Abstract No. 1519. 
(118) Reardon, D.A., et al. Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma. Cancer, 2004, 103(2), 329-338. 
(122) Beaney, R.P., et al., Therapeutic potential of antidepressants in malignant glioma: clinical experiment with chlorimipramine. Proceedings of the American Society of Clinical Oncology, 2005, Abstract #1535.
(123) Bili, A., Eguven, M. Oktem, G., et al. Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma. Int. J. Oncol, 2008, 32(4), 829-839. 
(124) Michelakis, E. D., Sutendra, G., Dromparis, P., et al. Metabolic modulation of glioblastoma with dichloroacetate. Science Translational Medicine, 2010, 2 (31), 1-8. 
(125) Kumar, K., Wigfield, S., Gee, H. E., et al. Dichloroacetate reverses the hypoxic adaptation to bevacizumab and enhances its anti-tumor effects in mouse xenografts. Journal of Molecular Medicine, 2013, 91(6), 749-58. 
(305) Jutten, Barry et al. “EGFR overexpressing cells and tumors are dependent on autophagy for growth and survival.” Radiotherapy and Oncology 108.3 (2013): 479-483. 
(316) Recchia, Francesco et al. “Interleukin-2 and 13-cis retinoic acid as maintenance therapy in advanced ovarian cancer.” International journal of oncology 27.4 (2005): 1039-1046.

Fine! I hope you enjoyed reading, I have been as faithful as possible. A second part of the chapter is coming very soon!