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Combinations for the treatment of neoplasms using quiescent cell targeting and inhibitors of mitosis

a technology of mitosis inhibitors and quiescent cells, which is applied in the direction of antineoplastic agents, medical preparations, pharmaceutical non-active ingredients, etc., can solve the problems of cancer recurrence upon re-entry, adverse effects of both anticancer therapies and radiation treatments, and cannot be predicted, so as to improve survival, improve the effect of outcome and reduce the severity

Inactive Publication Date: 2019-09-26
FELICITEX THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a combination treatment for cancer that uses a drug called a DYRK1 inhibitor. This treatment can improve outcomes by increasing survival, reducing the severity of the cancer, delaying or eliminating recurrence, and reducing side effects of the primary treatment. The combination treatment may also increase the fraction of cancer cells that die through a process called apoptosis. The inhibitor of mitosis, which is the combination treatment also reduces the fraction of cancer cells that would be found without the inhibitor. This inhibitor targets a protein called DYRK1, which is involved in cancer cell survival. Overall, this combination treatment has the potential to improve the effectiveness of cancer treatment.

Problems solved by technology

Both anticancer therapeutics and radiation treatments produce adverse effects.
Upon reduction in doses or discontinuation of treatment, however, the surviving quiescent cancer cells can cause cancer recurrence upon re-entry to the cell cycle, the timing of which cannot be predicted.
Yet, despite a growing appreciation of the importance of cancer cell quiescence, this issue remains unaddressed clinically.

Method used

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  • Combinations for the treatment of neoplasms using quiescent cell targeting and inhibitors of mitosis
  • Combinations for the treatment of neoplasms using quiescent cell targeting and inhibitors of mitosis
  • Combinations for the treatment of neoplasms using quiescent cell targeting and inhibitors of mitosis

Examples

Experimental program
Comparison scheme
Effect test

example 1

tion of Fraction of Quiescent Cancer Cells within a Population

[0107]The following cell lines were obtained from ATCC and cultured according to the ATCC recommendations: DMS273—small cell lung cancer cell line; H1975—non-small cell lung cancer cell line harboring L858R and T790M mutations in EGFR TK; A549—a non-small cell lung cancer cell line with wild type EGFR; LNCap—prostate cancer cell line; SW620—colon cancer cell line; MiaPaCa2—pancreatic cancer cell line; PANC1—pancreatic cancer cell line; OVCAR3—ovarian cancer cell line; SK-OV-3—ovarian cancer cell line.

[0108]Cell cultures were seeded into 6-well plates at 3×105-6×105 cells / well; the plated number of cells depended on cell size and rate of proliferation, aiming for approximately 50% confluency. After seeding, the cells were allowed to attach for 24 hours while incubated at 37° C. in a humidified 5% CO2 atmosphere, and then treated with compounds for desired amount of time (usually 24 hours) incubating under same conditions. ...

example 2

rocedure for the Cell Viability Assays

[0109]For viability analysis, cells were seeded into 96-well plates at 2×103-6×103 cells / well; the plated number of cells depended on cell size and rate of proliferation aiming for approximately 50% confluency. After seeding, the cells were allowed to attach for 24 hours incubated at 37° C. in a humidified 5% CO2 atmosphere.

[0110]The treatments were performed using at least 6 different concentrations of a compound in 1:3 serial dilutions in DMSO such that the DMSO concentration in the cell medium was 2 incubator at 37° C. Treatments were performed in triplicate. Results were analyzed by CellTiter-Glo™ Luminescent Cell Viability Assay (Promega, cat. # G7571) according to the manufacturer's instructions using Spectra MAX Gemini Spectrophotometer (Molecular Devices).

example 3

on of a Molecule Effective Against Quiescent Cancer Cells with Paclitaxel

[0111]SW620 cells were cultured, treated, and analyzed as described in Examples 1 and 2. The highest concentration of paclitaxel used in this assay was 100 nM and the concentrations of Compound I-5 were 2 μM and 4 accordingly. The observed EC50 values of paclitaxel were 8.1 nM when Compound I-5 was not present, 2.3 nM when Compound I-5 was present at a concentration of 2 and 0.2 nM when Compound I-5 was present at a concentration of 4 μM. See FIG. 3.

[0112]DMS273 cells were cultured, treated, and analyzed as described in Examples 1 and 2. The highest concentration of paclitaxel used in this assay was 10 nM and the concentrations of Compound I-7 were 2 μM and 4 μM. The observed EC50 values of paclitaxel were 2.7 nM when Compound I-7 was not present, 1.9 nM when Compound I-7 was present at a concentration of 2 μM, and 0.9 nM when Compound I-7 was present at a concentration of 4 μM. See FIG. 4.

[0113]LNCap cells wer...

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PUM

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Abstract

The present invention provides compositions and methods for the treatment of neoplasms, in particular, by targeting of quiescent cancer cells with therapeutic agents in combination with other treatments effective against certain neoplastic conditions, in particular, anti-cancer treatment with therapeutic agents that are inhibitors of mitosis (a mitotic inhibitor).

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional of U.S. patent application Ser. No. 15 / 488,143, filed Apr. 14, 2017, which itself claims the benefit of U.S. Provisional Patent Application No. 62 / 323,583, filed Apr. 15, 2016, each of which is incorporated by reference herein in its entirety.BACKGROUND OF THE INVENTION[0002]Cancer cell quiescence, effectively a cell in a state of sleep, has been recognized recently as a major mechanism of the resistance of cancer cells to treatments and for providing a pathway for disease recurrence. This quiescence, alternatively called cellular dormancy, is due to arrest at G0 phase of the cell cycle. Typically, a cell enters a cell cycle from gap phase 1 (G1), as shown in FIG. 1. After a synthesis phase (S) and a short pre-mitotic interval (G2), the cell divides by mitosis (M) followed by a return to G1. Instead of G1 however, a cell can enter cellular dormancy or quiescence, designated as the G0 phase. Cancer cells ca...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519A61K31/496A61K45/06A61K31/337A61K31/475
CPCA61K45/06A61K31/337A61K31/519A61K31/475A61K31/496A61K31/517A61K31/506A61P35/00A61K2300/00A61K47/54
Inventor VILENCHIK, MARIAFRID, MICHAELKUZNETSOVA, ALEXANDRAGANKIN, YURIYDUEY, MARC
Owner FELICITEX THERAPEUTICS
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