PORTUGESE TEXT:
[http://www.freshpatents.com/-dt20090423ptan20090105343.php?type=description
1. TERAPIA DO CANCRO E MEDICAÇÃO- http://medicaltranslationstraducoesapplicati.blogspot.com/2009/05/aaaaa-httpwww.html
ENGLISH TEXT
CANCER THERAPY AND MEDICAMENTS THEREFOR - http://medicaltranslationstraducoesapplicati.blogspot.com/2009/05/cancer-therapy-and-medicaments-therefor_24.html
domingo, 24 de maio de 2009
TERAPIA DO CANCRO E MEDICAÇÃO
TERAPIA DO CANCRO E MEDICAÇÃO
http://www.freshpatents.com/-dt20090423ptan20090105343.php
USPTO Application #: 20090105343
Sumário: A presente invenção descreve uma nova terapia do cancro, em particular, mas não exclusivamente: da próstata, bexiga e mama. Refere também composições e medicamentos para a terapia. Por um lado é descrito um método de tratamento de um paciente atormentado de cancro, que compreende administração de um conjunto terapêutico eficaz de um receptor nuclear de ligação e um inibidor de histona deacetilase (inibidor HDAC, IDH) em que o citado receptor nuclear de ligação não é um conector para o receptor da vitamina D. (fim do sumário )
Agente: Paul D Greeley Ohlandt, Greeley, Ruggiero & Perle, LLC - Stamford, CT, US
Inventores:James Moray Campbell, Christopher Bunce, Lyndon Gommersall, Donna Peehl
USPTO Applicaton #: 20090105343 - Class: 514563 (USPTO)
Terapia do cancro e medicação – descrição/queixas
The Patent Description & Claims data abaixo pertence à USPTO Patent Application 20090105343 - Terapia do cancro e medicação
Breve Descrição da Patente - Descrição completa da Patente -
Queixas dos clientes
A presente invenção descreve, por um lado, um novo aspecto da terapia do cancro, em particular, mas não exclusivamente, da próstata, bexiga e mama. Por outro lado, a invenção proporciona um método de redução da proliferação da/ou morte celular programada (e.g. apoptose) nas células neoplásticas.
O receptor nuclear (NR) super familiar é uma grande família (48 membros humanos) de ligação activada de transcrição de factores que, colectivamente, regulam múltiplos aspectos de proliferação e diferenciação Os NRs podem ser subdivididos em
• Receptores endócrinos clássicos que ligam ligadores com grande afinidade (receptores de androgénio (ERs) aos receptores de estrogéneo e receptor de vitamina D (VDR).
• Receptores órfãos adoptados que ligam ligadores com maior afinidade, i.é, receptores activados de proliferador peroxisome (PPARs), receptor de ácido biliar (FXR),, receptores de lípido X (PPARs), e receptor pregnano X (PXR).
o Receptores órfãos, para os quais ainda não foi identificado qualquer ligador.
As acções NR resultam em cancro. Foi previamente demonstrado que o androgénio agressivo das linhas de células independentes do cancro da próstata, apresentam frequentemente sensibilidade reduzida à acção antiproliferativa de uma variedade de ligadores de receptores nucleares tais como os RARs (receptores do ácido retinóico), PPAR e VDR
Estudos iniciais para investigar mecanismos que destroem a acção antiproliferativa NR focalizada no VDR como chave membro da família que responde aos sinais circunvizinhos e tem uma poderosa associação com o cancro da próstata. Proliferação e diferenciação das células da próstata normal epitelial é rigorosamente regulada in vitro e in vivo por 1α,25-dihidroxivitamina D3 (1α,25(OH)2D3 (com grande afinidade ao ligador de VDR) que transactiva um certo número de genes rotulados de antiproliferativos (incluindo o CDKI p21(wafI/cipI)), justificando assim ensaios clínicos no cancro da próstata dos pacientes. Contudo, a resposta antiproliferativa é reduzida a vários graus em alguns tumores da próstata. Estudos epidemiológicos múltiplos direccionaram ultimamente a incidência do cancro da próstata para baixos níveis de soro do precursor 1α,25(OH)2D3, como consequência do regime alimentar ou do meio envolvente. Para além disso, certos polimorfismos do VDR encontram-se associados com elevada incidência. Colectivamente, tais dados conduzem à iniciação ou progressão do cancro da próstata com redução na alimentação e/ou na resistência das células antiproliferativas aos efeitos do 1α,25(OH)2D3.
Os NRs partilham uma arquitectura comum, actuando como factores de transcrição, incluindo regiões delimitadas para o reconhecimento do DNA, ligação entre ligador e interacções de cofactores. O domínio de ligação do DNA- reconhece sequências nucleóides específicas (elementos de resposta). A ligação do ligador implica mudanças de conformação que abrem as ligações NR do co-repressor de proteínas (CoR) , e.g. NCoR2/SMRT e NCoR1 ao co-activador de proteínas (CoA). Associado a estas proteínas CoA ou CoR encontram-se as histonas acetiltransferases (HAT) e histonas deacetilases (HDAC), respectivamente, que formam, em conjunto, parte de grande activação ou de genes multiméricos ou complexos de repressão. Uma função destes complexos é regular um enfiamento de modificação de caudas de histona através de uma variedade de processos, incluindo acetilação, metilação e fosforilação, regulando assim a afinidade ao DNA. Complexos de repressão com actividade HDAC arrasta decondensação local de cromatina e reprime a activação de genes.
Diferenças nas acções do tecido específico NR têm sido atribuídas a padrões de expressão CoA/CoR , como por exemplo as acções específicas do parcial antagonista tamoxifeno estão dependentes da expressão CoA. Assim, a sensibilidade celular às acções NR é fortemente influenciada pela expressão CoA/CoR. Para além disso, estas interacções resultam em malignidade. Por exemplo, a variedade de estudos têm demonstrado que a sensibilidade NR ao ligador é desregulada em leucemia mielóide e, por alterações de CoA ou CoR.
Uma das mais conhecidas translocações cromossómicas envolvendo receptores nucleares em cancerogenia, ocorre em leucemia promielocítica aguda. A translocação que a origina ocorre, na maioria dos casos entre os cromossomas 15 e 17, criando um produto de fusão entre os genes PLM e RARE. A proteína (PML-RARα) resultante da fusão tem grande afinidade ao CoR NCoR1 e todavia retém inapropriadamente histona deacetilases em torno dos promotores das regiões reagentes ao gene RARE visado conduzindo a anormal silenciamento da pró diferenciação normal da sinalização retinóide. Também a fusão proteínica ablaciona as funções normais da proteína que inclui coactivação do gene supressor do tumor p53 e a promoção de apoptoses (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). Similarmente, no cancro da mama, o CoA AIB1 é bem descrito para ser superexpresso e, por conseguinte resultando inapropriadamente em sinalização ERα melhor (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, um receptor esteróide co-activador, amplificado em cancro da mama e do ovário. Ciência , 277: 965-968, 1997). O mecanismo molecular para 1α,25(OH)2D3 e insensibilidade no cancro da próstata são também e ainda pouco claros. Foi previamente demonstrado que o VDR nem é mutado nem há estudos da expressão do receptor que lhe digam respeito que estabeleçam uma relação clara entre o conteúdo VDR e o efeito antiproliferativo através de 1α,25(OH)2D3. De facto, as linhas de células do cancro da próstata PC-3 e DU 145 são insensíveis relativamente a 1α,25(OH)2D3 e contudo a transactivação VDR é mantida e até aumentada, já que é avaliada pela indução do gene CYP24, um gene VDR visado, poderosamente indutível. Os inventores mostraram previamente que o tratamento da linha de células do cancro da próstata (LNCaP, PC-3 e DU 145) com 1α,25(OH)2D3 e trichostatin A (TSA) ou butirato como inibidor HDAC , deram como resultado inibição do crescimento sinergético e indução de aptose, embora os alvos da activação do gene permaneçam pouco claros (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)).
É um dos objectivos da presente invenção, num dos seus aspectos, providenciar uma nova faceta da terapia do cancro e um medicamento ou combinação de medicamentos para uso na citada terapia.
Aaaaa
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.
http://www.freshpatents.com/-dt20090423ptan20090105343.php
USPTO Application #: 20090105343
Sumário: A presente invenção descreve uma nova terapia do cancro, em particular, mas não exclusivamente: da próstata, bexiga e mama. Refere também composições e medicamentos para a terapia. Por um lado é descrito um método de tratamento de um paciente atormentado de cancro, que compreende administração de um conjunto terapêutico eficaz de um receptor nuclear de ligação e um inibidor de histona deacetilase (inibidor HDAC, IDH) em que o citado receptor nuclear de ligação não é um conector para o receptor da vitamina D. (fim do sumário )
Agente: Paul D Greeley Ohlandt, Greeley, Ruggiero & Perle, LLC - Stamford, CT, US
Inventores:James Moray Campbell, Christopher Bunce, Lyndon Gommersall, Donna Peehl
USPTO Applicaton #: 20090105343 - Class: 514563 (USPTO)
Terapia do cancro e medicação – descrição/queixas
The Patent Description & Claims data abaixo pertence à USPTO Patent Application 20090105343 - Terapia do cancro e medicação
Breve Descrição da Patente - Descrição completa da Patente -
Queixas dos clientes
A presente invenção descreve, por um lado, um novo aspecto da terapia do cancro, em particular, mas não exclusivamente, da próstata, bexiga e mama. Por outro lado, a invenção proporciona um método de redução da proliferação da/ou morte celular programada (e.g. apoptose) nas células neoplásticas.
O receptor nuclear (NR) super familiar é uma grande família (48 membros humanos) de ligação activada de transcrição de factores que, colectivamente, regulam múltiplos aspectos de proliferação e diferenciação Os NRs podem ser subdivididos em
• Receptores endócrinos clássicos que ligam ligadores com grande afinidade (receptores de androgénio (ERs) aos receptores de estrogéneo e receptor de vitamina D (VDR).
• Receptores órfãos adoptados que ligam ligadores com maior afinidade, i.é, receptores activados de proliferador peroxisome (PPARs), receptor de ácido biliar (FXR),, receptores de lípido X (PPARs), e receptor pregnano X (PXR).
o Receptores órfãos, para os quais ainda não foi identificado qualquer ligador.
As acções NR resultam em cancro. Foi previamente demonstrado que o androgénio agressivo das linhas de células independentes do cancro da próstata, apresentam frequentemente sensibilidade reduzida à acção antiproliferativa de uma variedade de ligadores de receptores nucleares tais como os RARs (receptores do ácido retinóico), PPAR e VDR
Estudos iniciais para investigar mecanismos que destroem a acção antiproliferativa NR focalizada no VDR como chave membro da família que responde aos sinais circunvizinhos e tem uma poderosa associação com o cancro da próstata. Proliferação e diferenciação das células da próstata normal epitelial é rigorosamente regulada in vitro e in vivo por 1α,25-dihidroxivitamina D3 (1α,25(OH)2D3 (com grande afinidade ao ligador de VDR) que transactiva um certo número de genes rotulados de antiproliferativos (incluindo o CDKI p21(wafI/cipI)), justificando assim ensaios clínicos no cancro da próstata dos pacientes. Contudo, a resposta antiproliferativa é reduzida a vários graus em alguns tumores da próstata. Estudos epidemiológicos múltiplos direccionaram ultimamente a incidência do cancro da próstata para baixos níveis de soro do precursor 1α,25(OH)2D3, como consequência do regime alimentar ou do meio envolvente. Para além disso, certos polimorfismos do VDR encontram-se associados com elevada incidência. Colectivamente, tais dados conduzem à iniciação ou progressão do cancro da próstata com redução na alimentação e/ou na resistência das células antiproliferativas aos efeitos do 1α,25(OH)2D3.
Os NRs partilham uma arquitectura comum, actuando como factores de transcrição, incluindo regiões delimitadas para o reconhecimento do DNA, ligação entre ligador e interacções de cofactores. O domínio de ligação do DNA- reconhece sequências nucleóides específicas (elementos de resposta). A ligação do ligador implica mudanças de conformação que abrem as ligações NR do co-repressor de proteínas (CoR) , e.g. NCoR2/SMRT e NCoR1 ao co-activador de proteínas (CoA). Associado a estas proteínas CoA ou CoR encontram-se as histonas acetiltransferases (HAT) e histonas deacetilases (HDAC), respectivamente, que formam, em conjunto, parte de grande activação ou de genes multiméricos ou complexos de repressão. Uma função destes complexos é regular um enfiamento de modificação de caudas de histona através de uma variedade de processos, incluindo acetilação, metilação e fosforilação, regulando assim a afinidade ao DNA. Complexos de repressão com actividade HDAC arrasta decondensação local de cromatina e reprime a activação de genes.
Diferenças nas acções do tecido específico NR têm sido atribuídas a padrões de expressão CoA/CoR , como por exemplo as acções específicas do parcial antagonista tamoxifeno estão dependentes da expressão CoA. Assim, a sensibilidade celular às acções NR é fortemente influenciada pela expressão CoA/CoR. Para além disso, estas interacções resultam em malignidade. Por exemplo, a variedade de estudos têm demonstrado que a sensibilidade NR ao ligador é desregulada em leucemia mielóide e, por alterações de CoA ou CoR.
Uma das mais conhecidas translocações cromossómicas envolvendo receptores nucleares em cancerogenia, ocorre em leucemia promielocítica aguda. A translocação que a origina ocorre, na maioria dos casos entre os cromossomas 15 e 17, criando um produto de fusão entre os genes PLM e RARE. A proteína (PML-RARα) resultante da fusão tem grande afinidade ao CoR NCoR1 e todavia retém inapropriadamente histona deacetilases em torno dos promotores das regiões reagentes ao gene RARE visado conduzindo a anormal silenciamento da pró diferenciação normal da sinalização retinóide. Também a fusão proteínica ablaciona as funções normais da proteína que inclui coactivação do gene supressor do tumor p53 e a promoção de apoptoses (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). Similarmente, no cancro da mama, o CoA AIB1 é bem descrito para ser superexpresso e, por conseguinte resultando inapropriadamente em sinalização ERα melhor (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, um receptor esteróide co-activador, amplificado em cancro da mama e do ovário. Ciência , 277: 965-968, 1997). O mecanismo molecular para 1α,25(OH)2D3 e insensibilidade no cancro da próstata são também e ainda pouco claros. Foi previamente demonstrado que o VDR nem é mutado nem há estudos da expressão do receptor que lhe digam respeito que estabeleçam uma relação clara entre o conteúdo VDR e o efeito antiproliferativo através de 1α,25(OH)2D3. De facto, as linhas de células do cancro da próstata PC-3 e DU 145 são insensíveis relativamente a 1α,25(OH)2D3 e contudo a transactivação VDR é mantida e até aumentada, já que é avaliada pela indução do gene CYP24, um gene VDR visado, poderosamente indutível. Os inventores mostraram previamente que o tratamento da linha de células do cancro da próstata (LNCaP, PC-3 e DU 145) com 1α,25(OH)2D3 e trichostatin A (TSA) ou butirato como inibidor HDAC , deram como resultado inibição do crescimento sinergético e indução de aptose, embora os alvos da activação do gene permaneçam pouco claros (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)).
É um dos objectivos da presente invenção, num dos seus aspectos, providenciar uma nova faceta da terapia do cancro e um medicamento ou combinação de medicamentos para uso na citada terapia.
Aaaaa
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.
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.
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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.
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