公开(公告)号：US20110142827A1

公开(公告)日：2011-06-16

申请号：US12886027

申请日：2010-09-20

申请人： Martin Gleave ,  Gabriella Zupi

发明人： Martin Gleave ,  Gabriella Zupi

IPC分类号： A61K39/395 ,  A61P35/00

CPC分类号： C07K16/32 ,  A61K39/39558 ,  A61K2039/505 ,  C07K2317/24 ,  A61K2300/00

摘要： Agents that perturb the EGF signaling pathway and that are known to be useful in the treatment of cancer are found also to result in increased expression of the protein clusterin. Since clusterin can provide protection against apoptosis, this secondary effect detracts from the efficacy of the therapeutic agent. This is overcome using a combination of an agent that has known therapeutic efficacy against the cancer to be treated by perturbation of the EGF signaling pathway and that stimulates expression of clusterin as a secondary effect, and an oligonucleotide that is effective to reduce the amount of clusterin in cancer cells. For example, the agent may be an antibody specific for HER-2, a small molecule inhibitor of HER-2, an antisense oligonucleotide specific for HER-2, or a peptide agent capable of interfering with HER-2 protein. The oligonucleotide may be an antisense oligonucleotide or an RNAi oligonucleotide.

摘要翻译： 发现干扰EGF信号通路并且已知可用于治疗癌症的试剂也导致蛋白质簇的表达增加。 由于簇蛋白可以提供针对细胞凋亡的保护作用，所以这种二次效应会降低治疗剂的功效。 使用具有已知治疗功效的药剂与通过EGF信号通路的扰动来治疗并刺激簇蛋白表达作为次要作用的药物的组合克服，以及有效降低簇的量的寡核苷酸 在癌细胞中。 例如，该试剂可以是对HER-2特异的抗体，HER-2的小分子抑制剂，对HER-2特异性的反义寡核苷酸，或能够干扰HER-2蛋白质的肽试剂。 寡核苷酸可以是反义寡核苷酸或RNAi寡核苷酸。

公开(公告)号：US20090258089A1

公开(公告)日：2009-10-15

申请号：US12431997

申请日：2009-04-29

申请人： Martin Gleave ,  Paul S. Rennie ,  Hideaki Miyake ,  Colleen Nelson ,  Tobias Zellweger

发明人： Martin Gleave ,  Paul S. Rennie ,  Hideaki Miyake ,  Colleen Nelson ,  Tobias Zellweger

IPC分类号： A61K31/7088 ,  A61P35/00 ,  A61K33/24

CPC分类号： A61K31/7125 ,  A61K31/00 ,  A61K31/337 ,  A61K31/66 ,  A61K31/704 ,  A61K45/06 ,  A61K48/00 ,  C07K14/775 ,  A61K2300/00

摘要： Administration of antisense oligodeoxynucleotides (ODN) targeted against the testosterone-repressed prostate message-2 (TRPM-2) gene can reduce the amount of TRPM-2 in renal cell cancer (RCC) cells and other cancer cells, and as a result enhance chemosensitivity of these cells to chemotherapy agents and radiation. Thus, for example, the sensitivity of renal cell cancer cells to a chemotherapeutic agent can be increased by exposing renal cell cancer cells to a chemotherapeutic agent and an agent which reduces the amount of TRPM-2 in the renal cell cancer cells. This provides an improved method for treatment of renal cell cancer, which is generally resistant to treatment with known chemotherapy agents.

摘要翻译： 针对睾丸激素抑制前列腺消息-2（TRPM-2）基因的反义寡脱氧核苷酸（ODN）的施用可以减少肾细胞癌（RCC）细胞和其他癌细胞中TRPM-2的量，从而增强化学敏感性 的这些细胞对化疗药物和辐射。 因此，例如，可以通过将肾细胞癌细胞暴露于化疗剂和减少肾细胞癌细胞中TRPM-2的量的试剂来增加肾细胞癌细胞对化疗剂的敏感性。 这提供了治疗肾细胞癌的改进方法，其通常对已知化疗剂的治疗具有抗性。

公开(公告)号：US07592323B1

公开(公告)日：2009-09-22

申请号：US11276581

申请日：2006-03-06

申请人： Martin Gleave ,  Paul S. Rennie ,  Hideaki Miyake ,  Colleen Nelson

发明人： Martin Gleave ,  Paul S. Rennie ,  Hideaki Miyake ,  Colleen Nelson

IPC分类号： A61K31/70 ,  C07H21/04

CPC分类号： C12N15/1135 ,  A61K31/00 ,  A61K31/337 ,  A61K31/66 ,  A61K31/704 ,  A61K41/0038 ,  A61K45/06 ,  A61K48/00 ,  C07H21/00 ,  C07K14/775 ,  C12N15/113 ,  C12N2310/315 ,  C12N2310/321 ,  C12N2310/3341 ,  C12N2310/341 ,  C12N2310/346 ,  A61K2300/00 ,  C12N2310/3525

摘要： It has now been determined that antisense therapy which reduces the expression of TRPM-2 provides therapeutic benefits in the treatment of cancer. In particular, such antisense therapy can be applied in treatment of prostate cancer and renal cell cancer. Addition of antisense TRPM-2 ODN to prostatic tumor cells in vivo is effective for delaying the onset of androgen independence. Thus, prostate cancer can be treated in an individual suffering from prostate cancer by initiating androgen-withdrawal to induce apoptotic cell death of prostatic tumor cells in the individual, and administering to the individual a composition effective to inhibit expression of TRPM-2 by the tumor cells, thereby delaying the progression of prostatic tumor cells to an androgen-independent state in an individual Combined use of antisense TRPM-2 and taxanes synergistically enhances cytotoxic chemosensitivity of androgen-independent prostate cancer. In addition, it has also been found that antisense TRPM-2 has beneficial effect for other cancer types. Specifically, antisense TRPM-2 ODN enhances chemosensitivity in human Renal cell cancer, a normally chemoresistant disease with no active chemotherapeutic agent having an objective response rate higher than 10%. Radiation sensitivity is also enhanced when cells expressing TRPM-2 are treated with antisense TRPM-2 ODN. Thus, the antisense TRPM-2 ODNs can be used to enhance hormone sensitivity, chemosensitivity and radiation sensitivity of a variety of cancer types in which expression of TRPM-2 has been observed.

公开(公告)号：US07368436B2

公开(公告)日：2008-05-06

申请号：US09944326

申请日：2001-08-30

申请人： Martin Gleave ,  Paul S. Rennie ,  Hideaki Miyake ,  Colleen Nelson

发明人： Martin Gleave ,  Paul S. Rennie ,  Hideaki Miyake ,  Colleen Nelson

IPC分类号： A61K31/70 ,  C07H21/04 ,  C07H21/00

CPC分类号： C12N15/1135 ,  A61K31/00 ,  A61K31/337 ,  A61K31/66 ,  A61K31/704 ,  A61K41/0038 ,  A61K45/06 ,  A61K48/00 ,  C07H21/00 ,  C07K14/775 ,  C12N15/113 ,  C12N2310/315 ,  C12N2310/321 ,  C12N2310/3341 ,  C12N2310/341 ,  C12N2310/346 ,  A61K2300/00 ,  C12N2310/3525

摘要： It has been determined that antisense therapy which reduces the expression of TRPM-2 provides therapeutic benefits in the treatment of cancer, particularly prostate and renal cell cancers. Addition of antisense TRPM-2 ODN to prostatic tumor cells in vivo is effective for delaying the onset of androgen independence, thus prostate cancer can be treated by initiating androgen-withdrawal to induce apoptotic cell death of prostatic tumor cells in an individual, and administering a composition effective to inhibit expression of TRPM-2 by the tumor cells. Combined use of antisense TRPM-2 and taxanes synergistically enhances cytotoxic chemosensitivity of androgen-independent prostate cancer and in human Renal cell cancer. Radiation sensitivity is also enhanced when cells expressing TRPM-2 are treated with antisense TRPM-2 ODN. Thus, the antisense TRPM-2 ODNs can be used to enhance hormone sensitivity, chemosensitivity and radiation sensitivity of a variety of cancer types in which expression of TRPM-2 has been observed.

摘要翻译： 已经确定减少TRPM-2表达的反义治疗在治疗癌症，特别是前列腺和肾细胞癌方面提供了治疗益处。 反义TRPM-2 ODN在体内对前列腺肿瘤细胞的添加对于延缓雄激素独立性的发作是有效的，因此前列腺癌可以通过引发雄激素停药来诱导个体中前列腺肿瘤细胞的凋亡性细胞死亡，并施用 有效抑制肿瘤细胞表达TRPM-2的组合物。 结合使用反义TRPM-2和紫杉烷类物质协同增强雄激素非依赖性前列腺癌和人类肾细胞癌的细胞毒性化学敏感性。 当用反义TRPM-2 ODN处理表达TRPM-2的细胞时，辐射敏感性也增强。 因此，反义TRPM-2 ODN可用于增强已观察到TRPM-2表达的各种癌症类型的激素敏感性，化学敏感性和辐射敏感性。

公开(公告)号：US07297684B1

公开(公告)日：2007-11-20

申请号：US09619908

申请日：2000-07-19

申请人： Martin Gleave ,  Hideaki Miyake

发明人： Martin Gleave ,  Hideaki Miyake

IPC分类号： A01N43/04 ,  A61K31/70 ,  C07H21/04 ,  C12Q1/68 ,  C12N5/00

CPC分类号： C12N15/113 ,  A61K38/00 ,  C12N2310/315 ,  C12Q1/6886 ,  C12Q2600/106

摘要： A method is provided for treating hormone-regulated tumors (for example, breast and prostatic tumors) in mammals, including humans, by administration of an antisense ODN which is complementary to a portion of the gene encoding IGFBP-5. Using the Shionogi tumor model in vitro and in vivo, the administration of such an ODN was shown to reduce proliferation of tumor cells, and also to delay the progression to androgen independence. Thus, treatment of prostate cancer in mammals, including humans, and delay of the progression of prostate tumors to androgen independence is accomplished by administering to the mammal a therapeutically effective amount of an antisense oligodeoxynucleotide which is complementary to a portion of the nucleic acid sequence encoding IGFBP-5 and which hybridizes with such a sequence to inhibit expression of IGFBP-5. Specific antisense ODN's which are suitable for use in the method are GACCACGCTGATCACCAT (Seq. ID. No. 1), which is derived from the murine gene sequence, and CGCGGTGAGCAACACCAT (Seq. ID. No. 3) and AGGTCATGCAGCAGCCGC (Seq. ID No 4), which are derived from the human gene sequence.

摘要翻译： 提供了通过施用与编码IGFBP-5的基因的一部分互补的反义ODN来治疗哺乳动物（包括人）中激素调节的肿瘤（例如乳腺和前列腺肿瘤）的方法。 在体外和体内使用Shionogi肿瘤模型，这种ODN的施用显示可以减少肿瘤细胞的增殖，并且也延缓进展到雄激素的独立性。 因此，通过向哺乳动物施用治疗有效量的反义寡脱氧核苷酸来完成前列腺癌在包括人类的哺乳动物中的治疗以及前列腺肿瘤的进展延迟到雄激素独立性，所述反义寡核苷酸与编码的核酸序列的一部分互补 IGFBP-5，其与这样的序列杂交以抑制IGFBP-5的表达。 适用于该方法的特异性反义ODN可以衍生自鼠基因序列的GACCACGCTGATCACCAT（Seq.ID.1号）和CGCGGTGAGCAACACCAT（Seq.ID.3号）和AGGTCATGCAGCAGCCGC（Seq.ID No 4），其源自人基因序列。

公开(公告)号：US07285541B2

公开(公告)日：2007-10-23

申请号：US10646391

申请日：2003-08-21

申请人： Martin Gleave ,  Burkhard Jansen

发明人： Martin Gleave ,  Burkhard Jansen

IPC分类号： A61K48/00 ,  C07H21/02 ,  C07H21/04

CPC分类号： C12N15/113 ,  A61K31/712 ,  A61K38/00 ,  C12N2310/315 ,  C12N2310/321 ,  C12N2310/341 ,  C12N2310/346 ,  C12N2310/3525

摘要： Treatment of melanoma is achieved through reduction in the effective amount of clusterin in melanoma cells of in a mammalian subject, preferably a human. A therapeutic agent effective to reduce the effective amount of clusterin in the melanoma cells is administered to the subject. The therapeutic agent may be, for example, an antisense ODN or small inhibitory RNA (siRNA) compound targeted to clusterin. bcl-xL in a subject or cell line can also be regulated by administering to the subject or cell line an agent effective to modulate the amount of clusterin expression. In particular, in clusterin expressing cells, the expression of bcl-xL is down-regulated when the effective amount of clusterin is reduced. Such inhibition is significant because bcl-xL is known to act as an inhibitor of apoptosis.

摘要翻译： 黑素瘤的治疗通过在哺乳动物受试者，优选人中减少黑素瘤细胞中的聚集蛋白的有效量来实现。 向受试者施用有效降低黑素瘤细胞中的聚集蛋白有效量的治疗剂。 治疗剂可以是例如靶向簇蛋白的反义ODN或小的抑制性RNA（siRNA）化合物。 受试者或细胞系中的bcl-xL也可以通过向受试者或细胞系施用有效调节聚集蛋白表达量的试剂来调节。 特别地，在簇蛋白表达细胞中，当有效量的聚集蛋白降低时，bcl-xL的表达下调。 这种抑制是显着的，因为已知bcl-xL作为凋亡抑制剂。

公开(公告)号：US08759308B2

公开(公告)日：2014-06-24

申请号：US12845521

申请日：2010-07-28

申请人： Martin Gleave ,  Burkhard Jansen ,  Ioannis P Trougakos ,  Efstathios Gonos ,  Maxim Signaevsky ,  Eliana Beraldi

发明人： Martin Gleave ,  Burkhard Jansen ,  Ioannis P Trougakos ,  Efstathios Gonos ,  Maxim Signaevsky ,  Eliana Beraldi

IPC分类号： A61K48/00

CPC分类号： C12N15/113 ,  A61K31/712 ,  A61K38/00 ,  C12N2310/315 ,  C12N2310/321 ,  C12N2310/341 ,  C12N2310/346 ,  C12N2310/3525

摘要： RNAi sequences that are useful as therapeutics in the treatment of cancers of various types, including prostate cancer, sarcomas such as osteosarcoma, renal cell carcinoma, breast cancer, bladder cancer, lung cancer, colon cancer, ovarian cancer, anaplastic large cell lymphoma and melanoma; and Alzheimer's disease. These sequences target clusterin, IGFBP-5, IGFBP-2, both IGFBP-2 and -5 simultaneously, Mitf, and B-raf. The invention further provides for the use of these RNAi sequences in the treatment of cancers of various types, including prostate cancer, sarcomas such as osteosarcoma, renal cell carcinoma, breast cancer, bladder cancer, lung cancer, colon cancer, ovarian cancer, anaplastic large cell lymphoma and melanoma; and Alzheimer's disease, and a method of treating such conditions through the administration of the RNA molecules with RNAi activity to an individual, including a human individual in need of such treatment.

摘要翻译： 可用作治疗各种类型癌症的RNAi序列，包括前列腺癌，肉瘤如骨肉瘤，肾细胞癌，乳腺癌，膀胱癌，肺癌，结肠癌，卵巢癌，间变性大细胞淋巴瘤和黑素瘤 ; 和阿尔茨海默病。 这些序列同时靶向簇蛋白，IGFBP-5，IGFBP-2，IGFBP-2和-5两者，Mitf和B-raf。 本发明进一步提供这些RNAi序列用于治疗各种类型的癌症，包括前列腺癌，肉瘤如骨肉瘤，肾细胞癌，乳腺癌，膀胱癌，肺癌，结肠癌，卵巢癌，间变性大 细胞淋巴瘤和黑素瘤; 和阿尔茨海默病，以及通过向包括需要这种治疗的人的个体的个体施用具有RNAi活性的RNA分子来治疗这些病症的方法。

公开(公告)号：US08361981B2

公开(公告)日：2013-01-29

申请号：US12431997

申请日：2009-04-29

申请人： Martin Gleave ,  Paul S. Rennie ,  Hideaki Miyake ,  Colleen Nelson ,  Tobias Zellweger

发明人： Martin Gleave ,  Paul S. Rennie ,  Hideaki Miyake ,  Colleen Nelson ,  Tobias Zellweger

IPC分类号： A61K31/70 ,  C07H21/04

CPC分类号： A61K31/7125 ,  A61K31/00 ,  A61K31/337 ,  A61K31/66 ,  A61K31/704 ,  A61K45/06 ,  A61K48/00 ,  C07K14/775 ,  A61K2300/00

摘要： Administration of antisense oligodeoxynucleotides (ODN) targeted against the testosterone-repressed prostate message-2 (TRPM-2) gene can reduce the amount of TRPM-2 in renal cell cancer (RCC) cells and other cancer cells, and as a result enhance chemosensitivity of these cells to chemotherapy agents and radiation. Thus, for example, the sensitivity of renal cell cancer cells to a chemotherapeutic agent can be increased by exposing renal cell cancer cells to a chemotherapeutic agent and an agent which reduces the amount of TRPM-2 in the renal cell cancer cells. This provides an improved method for treatment of renal cell cancer, which is generally resistant to treatment with known chemotherapy agents.

公开(公告)号：US20120202873A1

公开(公告)日：2012-08-09

申请号：US13404741

申请日：2012-02-24

申请人： Martin Gleave ,  Burkhard Jansen ,  Ioannis P. Trougakos ,  Efstathios Gonos ,  Maxim Signaevsky ,  Eliana Beraldi

发明人： Martin Gleave ,  Burkhard Jansen ,  Ioannis P. Trougakos ,  Efstathios Gonos ,  Maxim Signaevsky ,  Eliana Beraldi

IPC分类号： C07H21/02 ,  A61P35/04 ,  A61K31/7105

CPC分类号： C12N15/113 ,  A61K31/712 ,  A61K38/00 ,  C12N2310/315 ,  C12N2310/321 ,  C12N2310/341 ,  C12N2310/346 ,  C12N2310/3525

摘要： RNAi sequences that are useful as therapeutics in the treatment of cancers of various types, including prostate cancer, sarcomas such as osteosarcoma, renal cell carcinoma, breast cancer, bladder cancer, lung cancer, colon cancer, ovarian cancer, anaplastic large cell lymphoma and melanoma; and Alzheimer's disease. These sequences target clusterin, IGFBP-5, IGFBP-2, both IGFBP-2 and -5 simultaneously, Mitf, and B-raf. The invention further provides for the use of these RNAi sequences in the treatment of cancers of various types, including prostate cancer, sarcomas such as osteosarcoma, renal cell carcinoma, breast cancer, bladder cancer, lung cancer, colon cancer, ovarian cancer, anaplastic large cell lymphoma and melanoma; and Alzheimer's disease, and a method of treating such conditions through the administration of the RNA molecules with RNAi activity to an individual, including a human individual in need of such treatment.

摘要翻译： 可用作治疗各种类型癌症的RNAi序列，包括前列腺癌，肉瘤如骨肉瘤，肾细胞癌，乳腺癌，膀胱癌，肺癌，结肠癌，卵巢癌，间变性大细胞淋巴瘤和黑素瘤 ; 和阿尔茨海默病。 这些序列同时靶向簇蛋白，IGFBP-5，IGFBP-2，IGFBP-2和-5两者，Mitf和B-raf。 本发明进一步提供这些RNAi序列用于治疗各种类型的癌症，包括前列腺癌，肉瘤如骨肉瘤，肾细胞癌，乳腺癌，膀胱癌，肺癌，结肠癌，卵巢癌，间变性大 细胞淋巴瘤和黑素瘤; 和阿尔茨海默病，以及通过向包括需要这种治疗的人的个体的个体施用具有RNAi活性的RNA分子来治疗这些病症的方法。

公开(公告)号：US07973017B2

公开(公告)日：2011-07-05

申请号：US11287334

申请日：2005-11-23

申请人： Martin Gleave

发明人： Martin Gleave

IPC分类号： A01N43/04 ,  C07H21/02 ,  C07H21/04 ,  C12Q1/68 ,  C12P19/34

CPC分类号： C12N15/113 ,  A61K31/713 ,  A61K38/00 ,  C07K2319/00 ,  C12N2310/11 ,  C12N2310/111 ,  C12N2310/3519 ,  C12N2310/51

摘要： Agents that reduce the amount of IGFBP-2 and/or IGFBP-5 and that are known to be useful in the treatment of cancer result in increased expression of the protein clusterin. Since clusterin can provide protection against apoptosis, this secondary effect detracts from the efficacy of the therapeutic agent. In overcoming this, the present invention provides a combination of therapeutic agents that is useful in the treatment of cancer. The combination includes an agent that reduces the amount of IGFBP-2 and/or IGFBP-5 and that stimulates expression of clusterin as a secondary effect, and an oligonucleotide that is effective to reduce the amount of clusterin in cancer cells. In some embodiments of the invention, the agent that reduces IGFBP-2 and/or IGFBP-5 is a bispecific antisense species. The oligonucleotide may be an antisense oligonucleotide or an RNAi oligonucleotide.

摘要翻译： 降低IGFBP-2和/或IGFBP-5的量并且已知可用于治疗癌症的药物导致蛋白质簇的表达增加。 由于簇蛋白可以提供针对细胞凋亡的保护作用，所以这种二次效应会降低治疗剂的功效。 克服这一点，本发明提供了可用于治疗癌症的治疗剂的组合。 该组合包括减少IGFBP-2和/或IGFBP-5的量并刺激簇蛋白表达作为次要作用的试剂，以及有效降低癌细胞中的簇蛋白的量的寡核苷酸。 在本发明的一些实施方案中，减少IGFBP-2和/或IGFBP-5的药剂是双特异性反义物质。 寡核苷酸可以是反义寡核苷酸或RNAi寡核苷酸。