Use of dianhydrogalactitol or derivatives or analogs thereof for treatment of pediatric central nervous system malignancies

Abstract

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of malignancies of the central nervous system in pediatric patients, including glioblastoma multiforme (GBM) high grade glioma, and medulloblastoma. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N7 methylation and that can induce double-stranded breaks in DNA. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide, cisplatin, and tyrosine kinase inhibitors; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol can be used together with other anti-neoplastic agents (e.g. cisplatin) and can possess additive or super-additive effects.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]The above-identified application claims the benefit of PCT Patent Application Serial No. PCT / US2016 / 058661 by J. A. Bacha et al., designating the United States, entitled “Use of Dianhydrogalactitol or Derivatives or Analogs Thereof for Treatment of Pediatric Central Nervous System Malignancies,” and filed on Oct. 26, 2016, which, in turn, claimed the benefit of U.S. Provisional Application Ser. No. 62 / 247,350, by J. A. Bacha et al., entitled “Use of Dianhydrogalactitol or Derivatives or Analogs Thereof for Treatment of Pediatric Central Nervous System Malignancies,” filed Oct. 28, 2015. The contents of both of the above-identified applications are hereby incorporated in their entirety by this reference.FIELD OF THE INVENTION[0002]This invention is directed to compositions and methods employing dianhydrogalactitol, diacetyldianhydrogalactitol, or derivatives or analogs thereof for the treatment of pediatric central nervous system malignanci...

AI Technical Summary

Benefits of technology

Dianhydrogalactitol demonstrates efficacy in inhibiting the growth of glioblastoma and medulloblastoma cells, overcoming resistance to existing chemotherapies, and providing improved survival and reduced side effects, making it a promising treatment for pediatric central nervous system malignancies.

Problems solved by technology

While many advances have been made from basic scientific research to improvements in practical patient management, there still remains tremendous frustration in the rational and successful discovery of useful therapies particularly for life-threatening diseases such as cancer, inflammatory conditions, infection, and other conditions.

However, from the tens of billions of dollars spent over the past thirty years supporting these programs both preclinically and clinically, only a small number of compounds have been identified or discovered that have resulted in the successful development of useful therapeutic products.

Unfortunately, many of the compounds that have successfully met the preclinical testing and federal regulatory requirements for clinical evaluation were either unsuccessful or disappointing in human clinical trials.

In other cases, chemical agents where in vitro and in vivo studies suggested a potentially unique activity against a particular tumor type, molecular target or biological pathway were not successful in human Phase II clinical trials where specific examination of particular cancer indications / types were evaluated in government sanctioned (e.g., U.S. FDA), IRB approved clinical trials.

In addition, there are those cases where potential new agents were evaluated in randomized Phase III clinical trials where a significant clinical benefit could not be demonstrated; such cases have also been the cause of great frustration and disappointment.

Finally, a number of compounds have reached commercialization but their ultimate clinical utility has been limited by poor efficacy as monotherapy (<25% response rates) and untoward dose-limiting side-effects (Grade III and IV) (e.g., myelosuppression, neurotoxicity, cardiotoxicity, gastrointestinal toxicities, or other significant side effects).

In many of those cases, the results did not realize a significant enough improvement to warrant further clinical development toward product registration.

Even for commercialized products, their ultimate use is still limited by suboptimal performance.

With so few therapeutics approved for cancer patients and the realization that cancer is a collection of diseases with a multitude of etiologies and that a patient's response and survival from therapeutic intervention is complex with many factors playing a role in the success or failure of treatment including disease indication, stage of invasion and metastatic spread, patient gender, age, health conditions, previous therapies or other illnesses, genetic markers that can either promote or retard therapeutic efficacy, and other factors, the opportunity for cures in the near term remains elusive.

For difficult to treat cancers, a patient's treatment options are often exhausted quickly resulting in a desperate need for additional treatment regimens.

GBM has an extremely poor prognosis, despite various treatment methods including open craniotomy with surgical resection of as much of the tumor as possible, followed by sequential or concurrent chemoradiotherapy, antiangiogenic therapy with bevacizumab, gamma knife radiosurgery, and symptomatic management with corticosteroids.

The tumor can start producing symptoms quickly, but occasionally is asymptomatic until it reaches an extremely large size.

The mass effect from the tumor and the surrounding edema may compress the ventricles and cause hydrocephalus.

This may be one cause of their resistance to conventional treatments and their high recurrence rate.

Because the grade of the tumor is based on the most malignant portion of the tumor, biopsy or subtotal tumor resection can result in undergrading of the tumor.

The treatment of GBM is extremely difficult due to several factors: (1) the tumor cells are very resistant to conventional therapies; (2) the brain is susceptible to damage using conventional therapy; (3) the brain has a very limited capacity for self-repair; and (4) many therapeutic drugs cannot cross the blood-brain barrier to act on the tumor.

However, such symptomatic therapy does nothing to slow the progression of the tumor, and, in the case of administration of phenytoin concurrently with radiation therapy, can result in substantial side effects including erythema multiforme and Steven-Johnson syndrome.

Whole brain radiotherapy does not improve the results when compared to the more precise and targeted three-dimensional conformal radiotherapy.

In the treatment of other malignancies, the addition of chemotherapy to radiation has resulted in substantial improvements in survival, but this has not yet proven to be the case for GBM.

However, TMZ is often ineffective due to drug resistance as the result of the catalytic activity of the enzyme O6-methylguanine-DNA methyltransferase (MGMT), which results in repair of the lesion at O6 of the guanine of DNA molecules.

Chemoresistance to TMZ as a result of the activity of MGMT is frequently associated with poor outcomes in TMZ-treated patients, and patients in whom TMZ or bevacizumab is ineffective are left with few if any treatment options.

Additionally, cancer stem cells (CSC) are a subpopulation of the tumor that resist therapy and give rise to relapse.

Although bevacizumab may retard the progression of the disease, the first-line use of bevacizumab does not improve overall survival in patients with newly diagnosed GBM (M. R. Gilbert et al., “A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma,”New Engl. J. Med. 370: 699-708 (2014)).

Additionally, unlike some other malignancies in which the use of bevacizumab results in a potentiation of chemotherapy, in GBM, the addition of chemotherapy to bevacizumab did not improve on results from bevacizumab alone.

This type of edema is difficult to distinguish from that due to tumor, and both may coexist.

However, patients in which both temozolomide and bevacizumab have been ineffective have few if any treatment options.

Although gene transfer therapy has the potential to kill cancer cells while leaving healthy cells unharmed, this approach has been beset with many difficulties in other diseases, including the possibility for induction of other types of malignancies and interference with the functioning of the immune system.

Although multidisciplinary treatment has improved the 5-year survival rates in children significantly, the prognosis for recurrent MB and HGG remains poor with median overall survival <1 year.

Temozolomide (TMZ) is frequently employed in the treatment of pediatric HGG; however, clinical evidence is lacking and poor outcomes due to high-expression of the repair protein O6-methylguanine-DNA methyltransferase (MGMT), which is correlated with TMZ resistance, have been reported.

Mutations in p53 in these groups, and especially in recurrent SHH, are correlated with treatment resistance and poor prognosis.

However, this does not reference the specific treatment of pediatric glioblastoma or pediatric medulloblastoma, and there are additional considerations, including tolerability of medications and the immaturity of the immune system response, that must be addressed in pediatric patients.

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