Combination Therapies Using Hdac Inhibitors

Inactive Publication Date: 2008-09-04
TOPOTARGET UK LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0028]The combination therapy can provide a therapeutic advantage in view of the differential toxicity associated with the two treatment modalities. More specifically, treatment with HDAC inhibitors can lead to hematologic toxicity, whereas chemotherapy treatments can be toxic to tissue adjacent the tissue site. As such, th

Problems solved by technology

From onset, malignant plasma cells arising from clonal expansion accumulate in the bone marrow, producing abnormally high levels of immunoglobulins.
Multiple myeloma is difficult to diagnose early because there may be no symptoms in early stage.
However, these are not effective long-term treatments.
In many patients, high-dose chemotherapy supported by autologous stem cell transplantation (ASCT) may prolong event-free survival if the procedure is performed within 12 months of initial diagnosis.
However almost all patients receiving high-dose chemotherapy and an autologous peripheral stem cell transplant will ultimately relapse.
In addition, the prognosis for those affected by these diseases is often poor, as the survival rates for lymphoma patients remain low.
In many cases, patients respond initially to such first-line treatments, but subsequently suffer a relapse, i.e., a tumor reappears or resumes growing.
Again, in many cases, patients initially respond to such additional treatments,

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0128]The effects of HDAC inhibitors in combination with standard chemotherapeutic agents were tested in vitro to determine the potential clinical use of an HDAC inhibitor (i.e., PXD-101), in combination chemotherapy. See, for example, the Data Annexes below.

[0129]WST-1 proliferation assays were used to assess the anti-proliferative effects of drug combinations. For example, four myeloma cell lines (e.g., JJN3, LP-1, RPMI-8226, U266), the HCT116 human colon carcinoma cell line, and the ovarian cell line, A2780, and its platinum-resistant subline, A2780 / cp7, among others, were used in the combination studies. A commercial program, CalcuSyn®, was employed to determine whether the combined effects are synergistic, antagonistic, or additive.

WST-1 Assay

[0130]Cells were cultured, exposed to PXD-101 alone or in combination with a chemotherapeutic agent, and incubated for a time, and the number of viable cells was then assessed using the Cell Proliferation Reagent WST-1 from Boehringer Mann...

example 2

Clonogenic Assay

[0156]A clonogenic assay was performed essentially as described (Jensen et al., 1993) to determine the anti-proliferative effects of combinations involving PXD-101, in particular a combination involving PXD-101 and 5-FU. In this assay, HCT116 or p388 cells were exposed to combinations of PXD-101 and 5-FU for the indicated times. Cells were then plated in 0.3% agar in 6 cm petri dishes with sheep red blood cells as feeder layer in triplicate, and were incubated at 37° C. Plates were counted after 14-21 days. A summary of the results is provided in Data Annex 6. Data Annex 7 and FIG. 3 present the data underlying this summary, and shows the synergy of PXD-101 and 5-FU in the clonogenic assay as calculated by CalcuSyn®.

[0157]Data Annex 6 demonstrates that combinations of PXD-101 and 5-FU are synergistic to strongly synergistic in both cell lines when PXD-101 and 5-FU were co-incubated for 24 hours and when PXD-101 was administered 24 hours after the administration of 5-...

example 3

In Vivo Studies

[0158]To investigate the tumour growth inhibitory effect of PXD-101 in a HCT116 colon cancer subcutaneous xenograft model (nu / nu mice), two PXD-101 doses were included, 60 and 100 mg / kg scheduled q1d×5 / week for 2 weeks. The chemo-sensitising effect of PXD-101 in combination with 5-FU was also investigated. The 5-FU dose was set at 15 mg / kg.

[0159]PXD101 caused significant tumour growth inhibition in a HCT-116 colon cancer xenograft model in nude mice. 5-FU was ineffective in the HCT116 model in the chosen dose regimen, which indicates suboptimal dosing.

[0160]FIG. 4 shows the chemo-sensitising effect of PXD101. HCT116 colon cancer xenograph. Daily i.p. treatments with PXD101 (morning) and 5-FU (afternoon). Mean / SEM, n=10(9).

[0161]Chemo-sensitising effect of PXD101 on 5-FU treatment was indicated. The results indicated synergistic effect of PXD101 and 5-FU after the first treatment cycle where single 5-FU therapy is ineffective at 15 mg / kg. FIG. 4 depicts a graph summari...

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Abstract

The present invention pertains to a method for treating cancer, such as lung cancer, multiple myeloma, lymphoma, and epithelial ovarian cancer, comprising the administration to a patient in need thereof a first amount or dose of a histone deacetylase (HDAC) inhibitor, such as PXD-101, and a second amount or dose of another chemotherapeutic agent, such as dexamethasone or 5-fluorouracil, or an epidermal growth factor receptor (EGFR) inhibitor, such as TarcevaÚ, wherein the first and second amounts or doses together comprise a therapeutically effective amount.

Description

RELATED APPLICATIONS[0001]This application is related to: U.S. provisional patent application 60 / 649,991 filed 3 Feb. 2005; and U.S. provisional patent application 60 / 735,662 filed 10 Nov. 2005; the contents of both of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to methods for treating cancer. More specifically, the present invention relates to methods for treating cancer, such as lung cancer, multiple myeloma, lymphoma, and epithelial ovarian cancer, in a subject, said methods comprising administering to a patient in need thereof a therapeutically effective amount of a histone deacetylase inhibitor (e.g., PXD-101 or its analogs), and a second amount or dose of a (i.e., another) chemotherapeutic agent (e.g., dexamethasone or 5-fluorouracil) and / or an epidermal growth factor receptor (EGFR) inhibitor (e.g., Tarceva®).BACKGROUND OF THE INVENTION[0003]A number of patents and publications are cited herein in orde...

Claims

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Application Information

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IPC IPC(8): A61K33/24A61K31/18A61K31/505A61K31/282A61K31/4353A61K31/337A61K31/704A61K31/56A61K31/53A61K31/66A61K31/517A61P35/00
CPCA61K31/18A61K31/24A61K31/337A61K45/06A61K31/196A61K33/24A61K31/7076A61K31/7068A61K31/706A61K31/573A61K31/555A61K31/138A61K31/198A61K31/4745A61K31/513A61K31/517A61K31/519A61K2300/00A61K31/475
Inventor LICHENSTEIN, HENRIJEFFERS, MIKEQIAN, XIAOZHANGSEHESTED, MAXWELLPETERSEN, KAMILLE DUMONGRITCHIE, JAMES
Owner TOPOTARGET UK LTD
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