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Formulations and methods for the treatment of cancers

a cancer and cancer technology, applied in the field of cancer treatment methods, can solve the problems of not leading to clinically acceptable remission, the origin of castration resistant prostate cancer cells or the interaction between heterogeneous subpopulations of prostate cancer cells contributing to castration resistant prostate cancer remains poorly understood, and the treatment of adt has not been successful

Inactive Publication Date: 2019-08-08
STEMIRNA THERAPEUTICS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides certain technical effects that improve upon existing technologies. These effects may include increased efficiency, enhanced functionality, improved performance, or other advantages. These technical effects can be realized through various methods and improvements made to the invention's design or construction. Ultimately, the invention offers better performance, reliability, or overall user experience.

Problems solved by technology

However, androgen deprivation therapies (ADT) including chemical castration and use of androgen receptor antagonists have had limited success, since the targeted tumors become refractory to treatment and progress into castration resistant prostate cancer.
Although many mechanisms have been reported to contribute to castration resistance, the origins of the castration resistant prostate cancer cell or the interactions between heterogeneous subpopulations of prostate cancer cells contributing to castration resistant prostate cancer remain poorly understood.
Unfortunately, these approaches have not led to clinically acceptable remission since, many prostate cancer patients undergoing androgen deprivation therapy eventually become refractory to the treatment, progressing into advanced castration resistant prostate cancer, which is insensitive to this line of treatment.
Overall, there is a deficiency in the art for combinatorial and / or synergistic approaches to treat cancers.

Method used

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  • Formulations and methods for the treatment of cancers
  • Formulations and methods for the treatment of cancers
  • Formulations and methods for the treatment of cancers

Examples

Experimental program
Comparison scheme
Effect test

example 1

Patterns of AR Expression in Clinical Castration-Resistant Prostate Cancer and Castration-Resistant (CR) Xenografts

[0044]About 100 castration resistant prostate cancer whole-mount (WM) or tissue microarray (TMA) slides were assayed for androgen receptor expression using two antibodies that recognize the N-terminal epitopes of the androgen receptor, which could detect both full-length androgen receptor and all c-terminal truncated androgen receptor variants. The results revealed interesting and striking heterogeneous patterns of androgen receptor expression. Of the tested clinical samples, 26 cases (25%) completely lacked androgen receptor expression. The remaining AR+ tumors showed highly heterogeneous androgen receptor expression with both AR+ and AR− / lo areas either inter-mingled with or frequently separated from each other (FIG. 1A). When ‘zoomed’ in, the androgen receptor-positive PCa cells showed 3 expression patterns: substantially nuclear (nuc-AR), substantially cytoplasmic (...

example 2

Molecular Changes in Secondary LNCaP Castration Resistant Prostate Cancer in Response to Enzalutamide Therapy

[0047]To test the efficacy of enzalutamide in reducing androgen-independent PCa tumor burden, therapy experiments were performed by treating mice bearing LNCaP AI-tumors with enzalutamide, administered by i.p. route. FIG. 4B revealed that enzalutamide suppressed growth of androgen-independent LNCaP for the first 6.5 weeks, suggesting that the upregulated nuc-AR (see FIG. 1C) is causally mediating the primary castration resistant prostate cancer in the LNCaP androgen-independent-tumor model. However, at about 7 weeks no further response to enzalutamide was observed (arrow, FIG. 4B) suggesting the emergence of enzalutamide-resistant tumors. These secondary castration resistant prostate cancer tumors were resistant to both surgical castration and enzalutamide as evidenced by western blotting analysis (FIG. 4C) and immune-histochemical analysis (FIG. 4D) for markers, androgen rec...

example 3

Castration of LAPC9 AD Tumors Leads to Decreased AR and Upregulation of Many CSC and Castration-Associated Molecules and Pathways

[0049]To determine the sensitivity of LAPC9 androgen-independent tumors to enzalutamide, therapy experiments were performed as described for the LNCaP primary AI tumors (FIG. 3). FIG. 4 shows that in sharp contrast to the observed reductions in tumor volume following Enzalutamide therapy, LNCaP primary androgen-independent tumors were refractory to enzalutamide administration (FIG. 4B). Western blotting (FIG. 4C) and immuno-histochemical (FIG. 4D) analysis revealed no expression of androgen receptors and PSA. FKBP5 levels were greatly diminished in both vehicle and treatment groups. On the other hand Enzalutamide treatment continued to express high levels of integrin α2, c-Myc, N-cadherin, Bcl-2, and p-ERK1 / 2 (FIG. 4C). To determine whether blocking alternate pathways regulated by any of these high expressing proteins, in the Enzalutamide resistant LAPC9 a...

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Abstract

The present invention is directed to a formulation for treating cancer comprising an androgen receptor signaling inhibitor and a B-cell-lymphoma-2 inhibitor, which may further comprising a Bromodomain-and-Extra-Terminal protein inhibitor or a phosphoinositide 3-kinase inhibitor.

Description

BACKGROUND OF THE INVENTIONField of the Invention[0001]The present invention relates generally to methods for the treatment of cancer. More specifically, the invention relates to methods of treating cancers, such as, using a combination therapy.Description of the Related Art[0002]Prostate cancer is an androgen-fueled malignancy and the androgen receptor (AR) represents the prime therapeutic target. However, androgen deprivation therapies (ADT) including chemical castration and use of androgen receptor antagonists have had limited success, since the targeted tumors become refractory to treatment and progress into castration resistant prostate cancer. Although many mechanisms have been reported to contribute to castration resistance, the origins of the castration resistant prostate cancer cell or the interactions between heterogeneous subpopulations of prostate cancer cells contributing to castration resistant prostate cancer remain poorly understood.[0003]An analysis of >20 normal...

Claims

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Application Information

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IPC IPC(8): A61K31/4166A61P35/00
CPCA61K31/4166A61P35/00A61K2300/00A61K31/437A61K31/551A61K31/496A61K31/4709
Inventor TANG, DEAN G.CHEN, XIN
Owner STEMIRNA THERAPEUTICS CO LTD
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