News Column

"Methods to Treat Cancer Using Cyclosporine and Cyclosporine Derivatives" in Patent Application Approval Process

June 26, 2014



By a News Reporter-Staff News Editor at Gene Therapy Weekly -- A patent application by the inventors DITTMAR, John (Leonia, NJ); ROTHSTEIN, Rodney J. (Maplewood, NJ); REID, Robert J.D. (New York, NY); PARSONS, Ramon (Manhasset, NY); MAURER, Matthew (New York, NY); SHAW, Jacquelyn (Brooklyn, NY), filed on October 18, 2013, was made available online on June 12, 2014, according to news reporting originating from Washington, D.C., by NewsRx correspondents (see also The Trustees Of Columbia University In The City Of New York).

This patent application is assigned to The Trustees Of Columbia University In The City Of New York.

The following quote was obtained by the news editors from the background information supplied by the inventors: "Breast Cancer is one of the major cancers affecting women with an estimated 200,000 new cases of invasive breast cancer in the US during 2010.sup.1. Although mortality rates have declined over the past decade, this disease still accounts for nearly 40,000 deaths annually.sup.1. PTEN deficient breast cancers show poor prognosis with a high rate of metastasis to distant organs. An important barrier to progress in treating this disease is the lack of effective drugs that attack cancer cells without harming the surrounding normal tissue. Cancer treatments that target differences in the molecular makeup of cancer cells show great promise, but these therapies are often limited because the molecular target is not uniformly present in an affected population. For example some breast cancers can be treated with herceptin, but this drug is only effective in the 15-20% of breast cancers that show amplification of HER2.sup.2,3. An important approach to overcoming such an obstacle is to define additional therapeutic targets to treat a broader set of the affected population, either alone or in combination with existing treatments."

In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventors' summary information for this patent application: "The inventors screened yeast using an over-expression system that they designed specifically to identify genetic interactions with over-expression of genes associated with cancers, for example, but not limited to, PTEN-deficient breast cancer. Among the target genes that the inventors identified is yeast cyclophilin (CPR1), the orthologue of human CPYA, peptidyl-prolyl cis-trans isomerase, a target of cyclosporin. The inventors tested cancer cell lines, for example, but not limited to, PTEN deficient cancer cell lines, for sensitivity to cyclosporin, and found a 10-fold increased sensitivity to the drug cyclosporine.

"In certain aspects, the invention provides a method to treat cancer in a subject in need of treatment therefor, the method comprising: contacting a PTEN negative cancer in a subject in need of treatment with a therapeutic amount of a cyclosporine, whereby the cancer is treated.

"In certain aspects, the invention provides a method to reduce growth of a cancer cell in a subject in need of treatment therefor, the method comprising: contacting a PTEN negative cancer cell in a subject in need of treatment with a therapeutic amount of a cyclosporine, whereby the growth of the cancer is reduced compared to PTEN positive cancer cells.

"In certain aspects, the invention provides a method to induce apoptosis of a cancer cell in a subject in need of treatment therefor, the method comprising: contacting a PTEN negative cancer cell in a subject in need of treatment with a therapeutic amount of a cyclosporine, whereby apoptosis of the cancer cell is induced and the subject is treated.

"In certain aspects, the invention provides a method to treat cancer in a subject in need of treatment therefor, the method comprising: administering to a subject diagnosed with a PTEN negative cancer a therapeutic amount of a cyclosporine, whereby the cancer is treated.

"In non-limiting embodiments, the cyclosporine may be selected among a number of naturally occurring cyclosporin molecules. A non-limiting example of such naturally occurring molecule is cyclosporine A. In other embodiments, the cyclosporine may be a cyclosporine derivative. In other embodiments, the cyclosporine derivative is a non-immunosuppressive derivative.

"In certain aspects, the invention provides a method to treat cancer in a subject in need of treatment therefor, the method comprising: contacting a PTEN negative cancer in a subject in need thereof with a therapeutic amount of sanglifehrin, whereby the cancer is treated.

"In certain aspects, the invention provides a method to reduce growth of a cancer cell in a subject in need thereof, the method comprising: contacting a PTEN negative cancer cell in a subject in need of treatment therefor with a therapeutic amount of sanglifehrin, whereby the growth of the cancer is reduced compared to PTEN positive cancer cells.

"In certain aspects, the invention provides a method to induce apoptosis of a cancer cell in a subject in need thereof, the method comprising: contacting a PTEN negative cancer cell in a subject in need thereof with a therapeutic amount of sanglifehrin, whereby apoptosis of the cancer cell is induced and the subject is treated.

"In certain aspects, the invention provides a method to treat cancer in a subject in need of treatment therefor, the method comprising: administering to a subject diagnosed with a PTEN negative cancer a therapeutic amount of sanglifehrin, whereby the cancer is treated.

"In certain embodiments, the cancer is PTEN negative cancer. In non-limiting embodiments, the PTEN negative cancer is breast cancer, prostate cancer, colon cancer, glioblastoma, endometrial cancer, lung cancer, thyroid cancer, lymphomas, ovarian cancer, or a combination thereof. In non-limiting embodiments the breast cancer is a triple negative breast cancer. In non-limiting embodiments, the prostate cancer is a hormone negative prostate cancer.

"In certain aspects the invention provides a method to treat a PTEN negative cancer in a subject in need of treatment therefor, the method comprising: contacting the PTEN negative cancer in the subject in need of treatment therefor with a therapeutic amount of an agent which inhibits cyclophilin activity, whereby the cancer is treated. In certain aspects the invention provides a method to reduce growth of a PTEN negative cancer cell in a subject in need thereof, the method comprising: contacting the PTEN negative cancer cell in the subject in need thereof with a therapeutic amount of an agent which inhibits cyclophilin activity, whereby the growth of the cancer is reduced or inhibited compared to PTEN positive cancer cells. In certain aspects the invention provides a method to induce apoptosis of a PTEN negative cancer cell in a subject in need thereof, the method comprising: contacting the PTEN negative cancer cell in the subject in need of treatment therefor with a therapeutic amount of an agent which inhibits cyclophilin activity, whereby apoptosis of the cancer cell is induced and the subject is treated. In certain aspects the invention provides a method to treat cancer in a subject suffering from a PTEN negative cancer, the method comprising: administering to the subject suffering from a PTEN negative cancer a therapeutic amount of an agent which inhibits cyclophilin activity, whereby the cancer is treated.

"In certain aspects the invention provides a method to treat cancer in a subject in need of treatment therefor, the method comprising: contacting an SFRS1 or pericentrin overexpressing cancer in a subject in need of treatment therefor with a therapeutic amount of an agent which inhibits cyclophilin activity, whereby the cancer is treated. In certain aspects the invention provides a method to reduce growth of a cancer cell in a subject in need thereof, the method comprising: contacting an SFRS1 or pericentrin overexpressing cancer cell in a subject in need of treatment therefor with a therapeutic amount of an agent which inhibits cyclophilin activity, whereby the growth of the cancer is reduced. In certain aspects the invention provides a method to treat cancer in a subject, the method comprising: administering to a subject suffering from an SFRS1 or pericentrin overexpressing cancer a therapeutic amount of an agent which inhibits cyclophilin activity, whereby the cancer is treated. In certain non-limiting embodiments, the cancer is an ovarian neoplasia. In certain non-limiting embodiments, the cyclophilin inhibitor is a cyclosporine derivative which is non-immunosuppressive.

"In certain embodiments, the methods of the invention consist essentially of contacting a cancer cell in a subject in need of treatment therefor with a therapeutic amount of an agent which inhibits cyclophilin activity, whereby the growth of the cancer cell is inhibited or reduced. In certain embodiments, the methods of the invention consist of contacting a cancer cell in a subject in need of treatment therefor with a therapeutic amount of an agent which inhibits cyclophilin activity, whereby the growth of the cancer cell is inhibited or reduced. In certain embodiments, the methods of the invention consist essentially of administering to a subject in need thereof a therapeutic amount of an agent which inhibits cyclophilin activity, whereby the growth of the cancer cell is inhibited or reduced. In certain embodiments, the methods of the invention consist of administering to a subject in need thereof a therapeutic amount of an agent which inhibits cyclophilin activity, whereby the growth of the cancer cell is inhibited or reduced.

"Non-limiting examples of agents used as cyclophilin inhibitors include naturally occurring cyclosporines, cyclosporine derivatives, sanglifehrins, for example, but not limited to, sanglifehrins A-D, or any combination thereof In non-limiting embodiments of the methods, the cyclosporine is a naturally occurring cyclosporine, for example, but not limited to, cyclosporine A. In non-limiting embodiments of the methods, the cyclosporine derivative is a non-immunosuppressive cyclosporine derivative. In non-limiting embodiments of the methods, the cyclosporine derivative is the agent of Formula I, the agent of Formula II, NIM-811, SCY-635, DEBIO-025, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or any combination thereof In non-limiting embodiments of the methods, the sanglifehrin is sanglifehrinA, sanglifehrinB, sanglifehrinC, sanglifehrinD, or any combination thereof

"In certain embodiments of the methods, the therapeutic amount of cyclosporine or cyclosporine derivative is administered in a combination with a therapeutic amount of a PARP inhibitor or a DNA cross-linking agent, or a combination thereof.

"In certain embodiments of the methods, the therapeutic amount of sanglifehrin is administered in a combination with a therapeutic amount of a PARP inhibitor or a DNA cross-linking agent, or a combination thereof

"In certain embodiments of the methods, the DNA cross-linking agent is cisplatin, mitomycin C, cyclophosphamide, chlorambucil, uramustine, ifosfamide, melphalan, bendamustine, carmustine, or any combination thereof

"In certain embodiments of the methods, the PARP inhibitor is olaparib.

"Non-limiting examples of PTEN negative cancers include breast cancer, prostate cancer, colon cancer, glioblastoma, endometrial cancer, lung cancer, thyroid cancer, lymphomas, ovarian cancer, and combinations thereof

BRIEF DESCRIPTION OF THE DRAWINGS

"FIG. 1 shows growth inhibition effects of cyclosporin A. Proliferation of three isogenic cancer cell lines using CsA. Cells were plated in 48 well plates and treated with drug for ten days before quantifying cell proliferation using crystal violet assays.

"FIG. 2 shows cancer cell panel of survival to Cyclosporin A. Cell survival and proliferation of multiple cancer cell lines tested when exposed to cyclosporin A. Cells were plated in 48 well plates and treated with drug for ten days before quantifying cell proliferation using crystal violet assays.

"FIG. 3 shows that PTEN null cells undergo apoptosis upon exposure to cyclosporin A. Cleaved caspase 3 western blotting indicates PTEN null cells are undergoing apoptosis when exposed to 5 uM cyclosporin A for 48 hours, while parental cells do not. The control used is breast cancer cell line MDAMB468 treated with 800 nM doxorubicin for 48 hours.

"FIG. 4 shows the structure of cyclosporine A. (SEQ ID NO:3)

"FIG. 5 shows the structure of cyclosporine A and two non-immunosuppressive cyclosporine derivatives: compound 211-810 (Formula I) and compound 209-825 (Formula II).

"FIG. 6A shows structure of Sanglifehrins A-D; FIG. 6B shows structure of cyclosporines (CsA: R1=CH.sub.2CH(CH.sub.3).sub.2, R2=CH.sub.3, R3=H, Alisporivir (DEBIO-025): R1=CH(CH.sub.3).sub.2, R2=CH.sub.2CH.sub.3, R3=CH.sub.3, SCY-635: R1=CH.sub.2C(CH.sub.3).sub.2OH, R2.dbd.CH.sub.3, R3=SCH.sub.2N(CH.sub.3).sub.2, NIM-811: R1=CH(CH.sub.3)CH.sub.2CH.sub.3, R2=CH.sub.3, R3=H) (Gregory M A, Bobardt M, Obeid S, Chatterji U, Coates N J, Foster T, Gallay P, Leyssen P, Moss S J, Neyts J, Nur-E-Alam M, Paeshuyse J, Piraee M, Suthar D, Warneck T, Zhang M Q, Wilkinson B. 'Preclinical characterisation of naturally occurring polyketide cyclophilin inhibitors from the sanglifehrin family. Antimicrob Agents Chemother.' Mar. 7, 2011. [Epub ahead of print].

"FIG. 7 shows a schematic representation of the method to identify human genes as pharmacological targets for inhibition in cancer cells, based on a synthetic dosage lethality screen in yeast.

"FIG. 8 shows cell growth inhibition by Tacrolimus on MEF10A cells. MCF10A wild type (WT) and PTEN knockout (PT-/-) cells were seeded into 48-well plate with density of 4000 cells/well. The next day, the growth medium was changed to a medium containing Tacrolimus. Medium containing 0.1% DMSO was used as negative control. Ninety-six (96) hours after treatment, the cells were stained with crystal violet for cell growth. The cell growth of negative control group is set as 100%.

"FIGS. 9A-9D show MCF10A wild type (WT) and PTEN knockout (PT-/-) cells were seeded into 48-well plate with density of 4000 cells/well. The next day, the growth medium was changed to a medium containing CsA (FIG. 9A) or an analog as depicted in each panel in FIG. 9B-D. Medium containing 0.1% DMSO was used as negative control. Ninety-six (96) hours after treatment, the cells were stained with crystal violet for cell growth. The cell growth of negative control group is set as 100%. Formula III is 8T2. Formula IV is RLY-001. Formula V is RLY-018. Formula VI is RLY-045. Formula VII is RLY-062.

"Formula VIII is RLY-070. FIG. 10A shows the results for MCF10A wild type (WT) and PTEN knockout (PT-/-) cells seeded into 48-well plates at a density of 4000 cells/well. The next day, the growth medium was changed to a medium containing Cyclosporine A (CsA) and the non-immunosuppressive Cyclosporine analog, NIM-811. Medium containing 0.1% DMSO was used as negative control. Ninety-six (96) hours after treatment, the cells were stained with crystal violet and measured for cell growth. Cell growth of the negative control group is set as 100%.

"FIG. 10B shows the results for MDA-MB-468 cells (PT-/-) seeded into 48-well plates at a density of 5000 cells/well. The next day, the growth medium was changed to medium containing CsA and NIM-811. Medium containing 0.1% DMSO was used as negative control. The medium was replenished once. Seven days after treatment, the cells were stained with crystal violet and measured for cell growth. Cell growth of the negative control group is set as 100%."

URL and more information on this patent application, see: DITTMAR, John; ROTHSTEIN, Rodney J.; REID, Robert J.D.; PARSONS, Ramon; MAURER, Matthew; SHAW, Jacquelyn. Methods to Treat Cancer Using Cyclosporine and Cyclosporine Derivatives. Filed October 18, 2013 and posted June 12, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=3132&p=63&f=G&l=50&d=PG01&S1=20140605.PD.&OS=PD/20140605&RS=PD/20140605

Keywords for this news article include: Genetics, Oncology, Apoptosis, Cyclosporins, Therapeutics, Breast Cancer, Women's Health, Cyclic Peptides, Cell Proliferation, Cancer Gene Therapy, The Trustees Of Columbia University In The City Of New York.

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Source: Gene Therapy Weekly


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