CANCER THERAPY AND MEDICAMENTS THEREFOR

USPTO Application #: 20090105343

http://medicaltranslationstraducoesapplicati.blogspot.com/2009/05/aaaaa-httpwww.html

Abstract: The present invention relates to a novel cancer therapy, particularly, but not exclusively, to a prostate, bladder and breast cancer therapy and to Compositions and medicaments for use in said therapy. In one aspect there is provided a method of treating a patient afflicted with cancer comprising administering to the patient a therapeutically effective amount of a nuclear receptor ligand and an HDAC (histone deacetylases) inhibitor wherein said nuclear receptor ligand is not a ligand for the vitamin D receptor. (end of abstract)

Agent: Paul D Greeley Ohlandt, Greeley, Ruggiero & Perle, LLC - Stamford, CT, US
Inventors: James Moray Campbell, Christopher Bunce, Lyndon Gommersall, Donna Peehl
USPTO Applicaton #: 20090105343 - Class: 514563 (USPTO)


Cancer therapy and medicaments therefor description/claims

The Patent Description & Claims data below is from USPTO Patent Application 20090105343, Cancer therapy and medicaments therefor.

Brief Patent Description - Full Patent Description - Patent Application Claims

The present invention relates in one aspect to a novel cancer therapy, particularly but not exclusively a prostate, bladder and breast cancer therapy and to compositions and medicaments for use in said therapy. In another aspect, the invention provides a method of reducing proliferation of and/or inducing programmed cell death (e.g. apoptosis) in neoplastic cells.

The nuclear receptor (NR) superfamily is a large family (48 human members) of ligand-activated transcription factors which collectively regulate multiple aspects of proliferation and differentiation. The NRs can be subdivided into


Classical endocrine receptors that bind ligands with high affinity, e.g., androgen receptor (AR), oestrogen receptors (ERs), vitamin D receptor (VDR)
Adopted orphan receptors that bind ligands with broader affinity e.g., Peroxisome proliferator activated receptors (PPARs), bile acid receptor (FXR), Lipid X receptors (LXRs) and pregnane X receptor (PXR).
Orphan receptors, for which no ligand has yet been identified or exists.

NR actions are disrupted in cancer. It has previously been demonstrated that aggressive androgen independent prostate cancer cell lines often display reduced sensitivity to the antiproliferative action of a variety of nuclear receptor ligands such as those for the RARs (retinoic acid receptors), PPAR and VDR. Initial studies to investigate mechanisms which disrupt NR antiproliferative action focused on VDR as a key member of the family which responds to environmental signals and has a strong association with prostate cancer. Proliferation and differentiation of normal prostate epithelial cells is acutely regulated in vitro and in vivo by 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3, high affinity ligand for VDR) which transactivates a number of anti-proliferative target genes (including the CDKI p21(wafI/cipI)), thereby justifying clinical trials in prostate cancer patients. However, the antiproliferative response is reduced to various degrees in some prostate tumours. Multiple epidemiological studies have now linked the incidence of prostate cancer to low serum levels of the 1α,25(OH)2D3 precursor, 25(OH)D3 as a result of either diet or environment. Furthermore, certain VDR polymorphisms are associated with elevated incidence. Collectively, such data link initiation or progression of prostate cancer with reduced dietary intake and/or cellular resistance to the antiproliferative effects of 1α,25(OH)2D3.

The NRs share a common architecture to act as transcription factors including defined regions for DNA recognition, ligand binding and cofactor interactions. The DNA-binding domain recognises specific nucleotide sequences (response elements). Ligand binding induces conformational changes that switch NR binding from co-repressor (CoR) proteins e.g. NCoR2/SMRT and NCoR1 to co-activator proteins (CoA). Associated with these CoA or CoR proteins are histone acetyltransferases (HAT) and histone deacetylases (HDAC), respectively, which together form part of large multimeric gene activation or repression complexes. One function of these complexes is to regulate a range of post-translational modifications of histone tails by a variety of processes including acetylation, methylation and phosphorylation, thereby regulating the affinity to DNA. Repression complexes with HDAC activity induce local decondensation of chromatin and repress gene activation.

Differences in tissue-specific NR actions have been attributed to altered CoA/CoR expression patterns, for example the cell-type specific actions of the ERα partial antagonist, tamoxifen is dependent upon CoA expression. Thus cellular sensitivity to NR action is strongly influenced by CoA/CoR expression. Furthermore these interactions are disrupted in malignancy. For example a variety of studies have demonstrated that NR sensitivity to ligand is dysregulated in myeloid leukaemia and breast cancer and, by alterations to either CoA or CoR activity.

One of the best known chromosomal translocations involving nuclear receptors in carcinogenesis occurs in acute promyelocytic leukaemia. The causative translocation in most cases occurs between chromosomes 15 and 17 creating a fusion product between the PML and the RARE genes. The resulting fusion protein (PML-RARα) has a higher affinity for the CoR NCoR1 and therefore inappropriately retains histone deacetylases around the responsive regions of RARE target gene promoters and leads to abnormal silencing of the normally pro-differentiating retinoid signalling. Also, the fusion protein ablates the normal functions of the PML protein, which include co-activation of the p53 tumour suppressor gene and promotion of apoptosis (Altucci, L. and Gronemeyer, H. Nuclear receptors in cell life and death. Trends Endocrinol. Metab, 12: 460-468, 2001.) (Altucci L, Nature Reviews Cancer 2001). Similarly in breast cancer the CoA AIB1 is well described for being overexpressed and thereby resulting in inappropriately enhanced ERα signalling (Anzick, S. L., Kononen, J., Walker, R. L., Azorsa, D. O., Tanner, M. M., Guan, X. Y., Sauter, G., Kallioniemi, O. P., Trent, J. M., and Meltzer, P. S. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science, 277: 965-968, 1997). The molecular mechanisms for 1α,25(OH)2D3-insensitivity in prostate cancer are as yet unclear. It has previously been demonstrated that the VDR is neither mutated nor have receptor expression studies established a clear relationship between VDR content and antiproliferative effect by 1α,25(OH)2D3. Indeed, PC-3 and DU 145 prostate cancer cell lines are relatively 1α,25(OH)2D3-insensitive and yet VDR transactivation is sustained and even enhanced, as measured by induction of CYP24 gene, a highly inducible VDR target gene. Previously the inventors have shown that co-treatment of prostate cancer cell lines (LNCaP, PC-3 and DU 145) with 1α,25(OH)2D3 plus either trichostatin A (TSA) or sodium butyrate (NaB) as an HDAC inhibitor, resulted in synergistic growth inhibition and induction of apoptosis although the targets of gene activation remained unclear (Rashid, S. F. et al. Synergistic growth inhibition of prostate cancer cells by 1α,25Dihydroxyvitamin D3 and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A. Oncogene 20, 1860-1872 (2001)).

It is an object of the present invention in one aspect to provide a novel cancer therapy and a medicament or combination of medicaments for use in said therapy.

According to a first aspect of the present invention there is provided a method of treating a patient afflicted with cancer comprising administering to the patient a therapeutically effective amount of a nuclear receptor ligand and an HDAC inhibitor wherein said nuclear receptor ligand is not a ligand for the vitamin D receptor.

The nuclear receptor ligand and HDAC inhibitor may be administered sequentially, concomitantly or combined as a single medicament.

According to a second aspect of the present invention, there is provided a method of reducing proliferation of or inducing programmed cell death in neoplastic cells comprising contacting said neoplastic cells with a combination of a first and a second medicament, the combination being one which up-regulates mRNA of both the nuclear receptor and at least one anti-proliferative target gene whereby to enhance antiproliferation and/or programmed cell death in said neoplastic cells, the first medicament being a nuclear receptor ligand and the second medicament being an HDAC inhibitor, except for the combination of 1α,25(OH)2D3 and TSA or NaB.

The present invention also resides in the use of a nuclear receptor ligand and an HDAC inhibitor in the manufacture of a medicament for the reduction or prevention of proliferation of neoplastic cells or for the induction of programmed cell death (eg. apoptosis) in said neoplastic cells, or in the manufacture of respective medicaments for concomitant or sequential administration, excluding the combination of 1α,25(OH)2D3 and TSA or NaB.

According to a third aspect of the present invention there is provided a method of reducing proliferation and/or inducing programmed cell death of neoplastic cells exhibiting abnormal expression or activity of a co-repressor protein, comprising contacting said cells with an HDAC inhibitor and an anti-proliferative and/or programmed cell death-inducing gene trans-activating factor, whereby to induce expression of said anti-proliferative and/or programmed-cell death-inducing gene.

According to a fourth aspect of the present invention, there is provided a synergistic combination of an HDAC inhibitor and a nuclear receptor ligand, other than a ligand for the VDR, for reducing proliferation of or inducing programmed cell death in neoplastic cells.