Combination therapies for treating cancers

A cancer, complex technology used in the field of combination therapy for the treatment of cancer, capable of addressing DNA damage, damage to non-malignant cells, mutations or breaks

Pending Publication Date: 2020-11-20
JACKSON LAB THE
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this combination has proven successful in targeting a variety of malignancies, most compounds used in combination with inhibitors of glycolysis are not tumor-specific and can therefore d

Method used

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  • Combination therapies for treating cancers
  • Combination therapies for treating cancers
  • Combination therapies for treating cancers

Examples

Experimental program
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preparation example Construction

[0054] In some embodiments, the composition is a pharmaceutical composition. Pharmaceutical compositions are combinations of active agents (such as glycolysis inhibitors and / or RAD51 complex inhibitors) with carriers (inert or active), making the compositions especially suitable for in vivo or ex vivo therapeutic use. A pharmaceutically acceptable carrier does not cause undesired physiological effects upon or when administered to a subject. The carrier in the pharmaceutical composition must also be acceptable in the sense of being compatible with and capable of stabilizing the active agent. One or more solubilizing agents can be used as a drug carrier to deliver the active agent. Examples of pharmaceutically acceptable carriers include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to obtain compositions that can be used as dosage forms. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose and sodium l...

Embodiment 1

[0072] Example 1: 2DG Reduces Tumor Burden in a Spontaneous Mouse Model of Lymphomagenesis SJL / J Mice Spontaneously Develop a Proliferative Disease Involving CD4+ T and B Cells Similar to Non-Hodgkin's Lymphoma And it is evident after one year of age (27, 28). It is thought that in this model, activated CD4 that secretes interleukin-21 + T cells drive B cell transformation (29). CD8a-deficient, and thus CD8+ deficient, SJL / J mice exhibit a markedly accelerated development of B-cell lymphoma without other changes in their phenotype (30). As any tumor requires energy for growth or maintenance, highly proliferative cells, such as cancer cells, rely on multiple means of ATP production, including glycolysis, to meet their energy needs (4), thus following cellular glucose uptake Blocking glycolysis in cancer cells as a first step should theoretically reduce tumor burden (6, 7).

[0073] To test the extent to which glycolytic inhibition by 2DG attenuates these spontaneously arisi...

Embodiment 2

[0078] Example 2: Lung Tumor PDX Models Show that Metabolic Differences, Not Proliferation, Determine Susceptibility to 2DG

[0079] The effect of 2DG was evaluated in a PDX (patient-derived xenograft) model of human lung cancer. Despite the understanding that 2DG primarily affects glycolysis, studies have shown that 2DG may interfere with other systems, such as the cell cycle, independently of its effect on metabolism (8, 32, 33). Changes in the cell cycle will affect the proliferation of cancer cells and ultimately tumor growth. To test whether 2DG affects glycolysis independently of proliferation, two species with similar growth kinetics ( Figure 2A ) but the glycolytic pathway used differently by PDX human lung cancers (TM00244 and TM00921) (Table 1).

[0080] Table 1: Pathway differences between TM00921 and TM00244 (INGENUITY / KEGG pathway)

[0081]

[0082]

[0083] A direct comparison of global gene expression between the two cancers revealed that one cancer, TM0...

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Abstract

Provided herein are compositions, methods, and kits for anticancer therapies using a glycolytic inhibitor and a RAD51 complex inhibitor.

Description

[0001] related application [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 765,028, filed August 17, 2018, and U.S. Provisional Application No. 62 / 634,400, filed February 23, 2018, under 35 U.S.C. § 119(e), each of which is Citations are incorporated herein in their entirety. Background technique [0003] Glycolysis is the major ATP production pathway in mammalian cells and can lead to lactic acid fermentation, or pyruvate oxidation, in which significantly fewer ATP molecules are produced per molecule of glucose metabolized (1). Cancer cells are characterized by a high rate of glycolysis compared to normal cells, resulting in excessive lactic acid fermentation despite inefficient ATP production, a phenomenon known as the Warburg effect (2-4). This effect, originally thought to be responsible for tumor formation, is now recognized as a key feature of tumor cells in several types of cancer (5, 6). [0004] Due to the increased use of glycol...

Claims

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Application Information

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IPC IPC(8): A61K31/7004A61P35/00A61K31/185A61K31/275
CPCA61K31/7004A61P35/00A61K31/185A61K31/275A61K45/06A61K2300/00A61K31/517A61K31/5377A61P35/02
Inventor M·G·哈希姆D·C·鲁普尼安
Owner JACKSON LAB THE
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