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Methods for treating neuroblastoma

a neuroblastoma and treatment method technology, applied in the field of cancer biology and medicine, can solve the problem of poor overall long-term survival of patients with high-risk diseases at approximately 50%, and achieve the effect of preventing ototoxicity or the risk thereof in the patien

Inactive Publication Date: 2019-02-14
CANCER PREVENTION PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for preventing ototoxicity in patients who may be at risk for it. This method involves testing the patient's genotype at a specific location in the ODC1 gene. If the result indicates a risk for ototoxicity, the patient is given a pharmaceutical therapy to reduce the risk. This can help to protect the patient's hearing and prevent the onset of hearing damage.

Problems solved by technology

Despite advances in treatments that include chemotherapy, surgery, radiation, high dose chemotherapy with stem cell rescue, antibody-based therapy, and biologic-based therapy, the overall long-term survival of patients with high risk disease remains poor at approximately 50%.

Method used

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  • Methods for treating neuroblastoma
  • Methods for treating neuroblastoma
  • Methods for treating neuroblastoma

Examples

Experimental program
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Effect test

example 1

Oral DFMO and Etoposide

[0237]The primary aim of the phase I clinical trial was to study the safety of the ODC inhibitor α-difluoromethylomithine (DFMO) alone and in combination with a cytotoxic chemotherapeutic drug in pediatric patients with refractory or recurrent NB. Etoposide was chosen for the combination, as it has reported efficacy in this patient group (Kushner et al., 2013) and is synergistic with DFMO in some cell models (Dorr et al., 1986). The secondary aims were to investigate the activity, pharmacokinetics and genetic and metabolic factors associated with ODC.

[0238]No dose-limiting toxicities (DLTs) or drug related serious adverse events (SAEs) were observed in this study. Study related (possibly, probably, and definitely related) toxicities observed during all cycles are summarized in Table 3. Those related to DFMO alone consisted of anemia (N=3), ANC decrease (N=2), decreased platelet count (N=2), ALT increase (N=1), AST increase (N=1), anorexia (N=1), constipation (...

example 2

inetics of DFMO in Children with NB

[0239]DFMO serum measurements were performed in all 21 patients. Samples were collected from patients prior to, and again at times 0.5, 1, 3, and 6 hours following drug administration on days 1 and 8 of the first cycle. DFMO serum samples were also collected from selected patients in the higher dose groups (750, 1000, 1500 mg / m2) during cycle 2. FIG. 4 shows the serum DFMO concentrations (mean and sd) in all patients receiving 750 mg / m2 (mean±standard deviation). DFMO doses were administered orally twice daily over a 21 day cycle. Subsequent cycles commenced the day following the last day of the previous cycle. Maximum DFMO concentrations, relative to dose, are reported in Table 4. Overall average serum DFMO concentrations ranged from 9.54 μg / mL (52.24 μM) in patients receiving 500 mg / m2 to 30.71 μg / mL (168.10 μM) in patients receiving 1500 mg / m2. The mean tmax occurred between 2.50 and 3.75 hours, in all dose groups. The mean AUC0-6h ranged from 3...

example 3

for Genetic and Metabolic Markers of Polyamine Metabolism and Pharmacodynamic (PD) Measures of DFMO Effect

[0241]FIG. 1 depicts the polyamine metabolic pathway and highlights the relationship between ODC genotypes (rs2302615 and rs2302616), affecting ODC expression, and their relationship to urinary polyamines. The figure shows the substrate relationships for the diamine and acetylpolyamine exporter (Xie et al., 1997; Uemura et al., 2008; Uemura et al., 2010), which include putrescine, monoacetylspermidine and diacetylspermine (DAS) but not spermidine or spermine. Levels of these exported amines might be expected to reflect changes in tissue ODC expression, as polyamine export is known as one component of polyamine homeostatic regulation (Gerner and Meyskens, 2004).

[0242]First morning void spot urines from each patient were evaluated for polyamines as described in Methods. Table 5 shows data (means±SD) at baseline (cycle 1, day 1) for seven metabolites in the polyamine pathway, inclu...

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Abstract

The present invention provides methods and kits a) for preventing and / or treating neuroblastoma (e.g., high-risk neuroblastoma) that is linked, in part, to high levels of ODC activity and increased cellular polyamine content, b) for predicting cancer patient survival, especially cancer patients whose cancer is linked, in part, to high levels of ODC activity and increased cellular polyamine contents, and c) for selecting treatment options for such patients based on the allelic nucleotide sequence or SNP at positions +263 and / or +316 of the ODC1 gene. The invention also provides, cancer treatment methods comprising the determination of the ODC1 genotype at the +263 and / or +316 positions, as a means to guide treatment selection, which includes, in some aspects the administration of pharmaceutically effective amounts of α-difluoromethylomithine (DFMO), either as a monotherapy or in combination with one or more other drugs. In addition, the present invention provides methods for preventing and / or treating patients that have been determined to have cancer stem cells, such as patients in cancer remission that are at risk for relapse.

Description

[0001]The present application claims the priority benefit of U.S. provisional application No. 62 / 115,413, filed Feb. 12, 2015 and U.S. provisional application No. 62 / 154,804, filed Apr. 30, 2015, the entire contents of which are incorporated herein by reference.[0002]The invention was made with government support under Grant Nos. R01 CA123065 and P50 CA095060 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION1. Field of the Invention[0003]The present invention relates generally to the fields of cancer biology and medicine. More particularly, it concerns methods for the diagnosis, prevention, and treatment of carcinomas and risk factors thereof.2. Description of Related Art[0004]Neuroblastoma (NB) is a deadly childhood cancer that arises from neural crest cells of the sympathetic nervous system. The average age at diagnosis is 17 months and 50-60% of patients present with metastatic disease. NB is a heterogeneo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/198A61P35/00C12Q1/6886
CPCA61K31/198A61P35/00C12Q1/6886A61K2300/00A61K45/06A61K31/192A61K31/203A61K31/415A61K31/616A61K31/69A61K31/7048C07K16/3084C12Q2600/106C12Q2600/156A61K39/39558A61K39/395A61K2039/505
Inventor GERNER, EUGENEBRUCKHEIMER, ELIZABETH
Owner CANCER PREVENTION PHARMA
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