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Rich66 · 08-18-2010, 10:34 AM

J Biol Chem. 2010 Aug 2. [Epub ahead of print]
Tumor-supportive and osteoclastogenic changes induced by breast cancer-derived factors are reversed by inhibition of {gamma}-secretase.

Fong JE, Le Nihouannen D, Komarova SV.
McGill University, Canada.

Abstract

During breast cancer metastasis to bone, tumor cells home to bone marrow, likely targeting the stem cell niche, and stimulate osteoclasts, which mediate osteolysis required for tumor expansion. Although osteoblasts contribute to the regulation of the hematopoietic stem cell niche and control osteoclastogenesis through production of pro-resorptive cytokine RANKL, their role in cancer metastases to bone is not fully understood. C57BL/6J mouse bone marrow cells were treated for 3-12 days with ascorbic acid (AA, 50 mug/mL), in the presence or absence of 10% medium conditioned by breast carcinoma cells MDA-MB-231, 4T1, or MCF7. Treatment with cancer-derived factors resulted in a sustained 40-60% decrease in osteoblast differentiation markers, compared to treatment with AA alone, and induced an osteoclastogenic change in the RANKL/OPG ratio. Importantly, exposure of bone cells to breast cancer-derived factors stimulated the subsequent attachment of cancer cells to immature osteoblasts. Inhibition of gamma-secretase using pharmacological inhibitors DAPT and Compound E completely reversed cancer-induced osteoclastogenesis as well as cancer-induced enhancement of cancer cell attachment, identifying gamma-secretase activity as a key mediator of these effects. Thus, we have uncovered osteoblasts as critical intermediary of pre-metastatic signaling by breast cancer cells and pinpointed gamma-secretase as a robust target for developing therapeutics potentially capable of reducing both homing and progression of cancer metastases to bone.

Int J Cancer. 2010 Aug 16. [Epub ahead of print]
Increased expression and serum levels of the stromal cell-secreted protein periostin in breast cancer bone metastases.

Contié S, Voorzanger-Rousselot N, Litvin J, Clézardin P, Garnero P.
Research Unit 664, Institut National de la Santé et de la Recherche Médicale, Lyon, F-69372 France.
Abstract

Periostin, a matricellular protein, is overexpressed in the stroma of several cancers. The aim of this study was to investigate more specifically whether periostin expression is associated with bone metastases from breast cancer and to determine its source in the affected bone. Nude mice were inoculated with human MDA-B02 breast cancer cells. Bone metastases-bearing mice were treated with zoledronic acid -an antiresorptive drug- or vehicle. Bone metastases were examined for tumor- and stroma-derived periostin expression by Q-PCR with human and mouse specific primers, and immunohistochemistry. Serum periostin and conventional bone turnover markers were also measured. MDA-B02 cells did not express periostin both in vitro and in vivo. However, mouse-derived periostin was markedly overexpressed (8-fold) in metastatic legs compared to non inoculated mice. Serum periostin levels were also markedly increased in metastatic mice and correlated with in situ expression levels. Immunostaining showed that periostin derived from the environing stromal cells of bone metastasis. Bone turnover blockade by zoledronic acid markedly decreased osteolytic lesions but only slightly modulated serum periostin levels. Bone metastases from breast cancer induce overexpression of periostin by surrounding stromal cells. Periostin could be a biochemical marker of the early stromal response associated to breast cancer bone metastasis formation.

PMID: 20715172 [PubMed - as supplied by publisher]

Drug Shows Promise for Castration-Resistant Prostate Cancer

John Schieszer
September 24 2010

LINK

CHICAGO—Alpharadin, an investigational agent, may relieve pain and improve survival in men with metastatic castration-resistant prostate cancer (CRPC), according to data presented at the American Society of Clinical Oncology annual meeting.
“This is a bone-seeking agent that is a first-in-class [medication],” said principal investigator Sten Nilsson, MD, Professor of Oncology at Karolinska University in Stockholm, Sweden. “It delivers a very, very strong cell killing activity. It also kills all cells irrespective of cell cycle phase and receptor expression. So, I think this is the dramatic advantage with this new pharmaceutical.”
Alpharadin is a calcium mimetic, alpha-emitting nuclide, which has a potent and highly targeted anti-tumor effect on bone metastases.
Dr. Nilsson and his colleagues analyzed data from two open-label phase 1 trials (total of 37 patients) and three double-blind, placebo-controlled phase 2 trials (total of 255 patients). All men had CRPC with bone metastases. In these trials, patients experienced significant improvement in bone markers and decreases in PSA levels and pain. In one of the placebo-controlled trials, median overall survival was greater in the alpharadin groups compared with placebo recipients (65 vs. 46 weeks).
The uptake of alpharadin into bone metastases occurs rapidly. In a separate analysis of data from a phase 1 pharmacokinetic and biodistribution study, the researchers found that alpharadin accumulates in bone metastases as early as 10 minutes from the time of injection.
In addition, the drug exhibits minimal activity in the kidneys, liver, or other internal organs. Of the 292 patients in the phase 1 and 2 trials, fewer than 1% experienced CTC grade 4 hematological toxicity, about 4% experienced grade 3 anemia, and fewer than 3% of the patients experienced grade 3 platelets, neutrophils or white blood cells. The most common adverse events seen in all studies were nausea (33% of patients), bone pain (30%), fatigue (26%), diarrhea (26%), vomiting (20%), and constipation (20%). The researchers observed no signs of renal or hepatic toxicity.
“This pharmaceutical has proven to be very, very safe,” Dr. Nilsson said. “It has a benign side effect profile. It gives very little toxicity to the bone marrow, which is the main risk organ in this disease. It is excreted in the bile and intestines so we don't see any toxic effects on the kidneys.”
Researchers are evaluating alpharadin in a global phase 3, randomized, double-blind, multi-dose, placebo-controlled international clinical trial in men with CRPC with bone metastases.

08-18-2010, 10:34 AM	#2
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Bone mets J Biol Chem. 2010 Aug 2. [Epub ahead of print] Tumor-supportive and osteoclastogenic changes induced by breast cancer-derived factors are reversed by inhibition of {gamma}-secretase. Fong JE, Le Nihouannen D, Komarova SV. McGill University, Canada. Abstract During breast cancer metastasis to bone, tumor cells home to bone marrow, likely targeting the stem cell niche, and stimulate osteoclasts, which mediate osteolysis required for tumor expansion. Although osteoblasts contribute to the regulation of the hematopoietic stem cell niche and control osteoclastogenesis through production of pro-resorptive cytokine RANKL, their role in cancer metastases to bone is not fully understood. C57BL/6J mouse bone marrow cells were treated for 3-12 days with ascorbic acid (AA, 50 mug/mL), in the presence or absence of 10% medium conditioned by breast carcinoma cells MDA-MB-231, 4T1, or MCF7. Treatment with cancer-derived factors resulted in a sustained 40-60% decrease in osteoblast differentiation markers, compared to treatment with AA alone, and induced an osteoclastogenic change in the RANKL/OPG ratio. Importantly, exposure of bone cells to breast cancer-derived factors stimulated the subsequent attachment of cancer cells to immature osteoblasts. Inhibition of gamma-secretase using pharmacological inhibitors DAPT and Compound E completely reversed cancer-induced osteoclastogenesis as well as cancer-induced enhancement of cancer cell attachment, identifying gamma-secretase activity as a key mediator of these effects. Thus, we have uncovered osteoblasts as critical intermediary of pre-metastatic signaling by breast cancer cells and pinpointed gamma-secretase as a robust target for developing therapeutics potentially capable of reducing both homing and progression of cancer metastases to bone. Int J Cancer. 2010 Aug 16. [Epub ahead of print] Increased expression and serum levels of the stromal cell-secreted protein periostin in breast cancer bone metastases. Contié S, Voorzanger-Rousselot N, Litvin J, Clézardin P, Garnero P. Research Unit 664, Institut National de la Santé et de la Recherche Médicale, Lyon, F-69372 France. Abstract Periostin, a matricellular protein, is overexpressed in the stroma of several cancers. The aim of this study was to investigate more specifically whether periostin expression is associated with bone metastases from breast cancer and to determine its source in the affected bone. Nude mice were inoculated with human MDA-B02 breast cancer cells. Bone metastases-bearing mice were treated with zoledronic acid -an antiresorptive drug- or vehicle. Bone metastases were examined for tumor- and stroma-derived periostin expression by Q-PCR with human and mouse specific primers, and immunohistochemistry. Serum periostin and conventional bone turnover markers were also measured. MDA-B02 cells did not express periostin both in vitro and in vivo. However, mouse-derived periostin was markedly overexpressed (8-fold) in metastatic legs compared to non inoculated mice. Serum periostin levels were also markedly increased in metastatic mice and correlated with in situ expression levels. Immunostaining showed that periostin derived from the environing stromal cells of bone metastasis. Bone turnover blockade by zoledronic acid markedly decreased osteolytic lesions but only slightly modulated serum periostin levels. Bone metastases from breast cancer induce overexpression of periostin by surrounding stromal cells. Periostin could be a biochemical marker of the early stromal response associated to breast cancer bone metastasis formation. PMID: 20715172 [PubMed - as supplied by publisher] Drug Shows Promise for Castration-Resistant Prostate Cancer John Schieszer September 24 2010 LINK CHICAGO—Alpharadin, an investigational agent, may relieve pain and improve survival in men with metastatic castration-resistant prostate cancer (CRPC), according to data presented at the American Society of Clinical Oncology annual meeting. “This is a bone-seeking agent that is a first-in-class [medication],” said principal investigator Sten Nilsson, MD, Professor of Oncology at Karolinska University in Stockholm, Sweden. “It delivers a very, very strong cell killing activity. It also kills all cells irrespective of cell cycle phase and receptor expression. So, I think this is the dramatic advantage with this new pharmaceutical.” Alpharadin is a calcium mimetic, alpha-emitting nuclide, which has a potent and highly targeted anti-tumor effect on bone metastases. Dr. Nilsson and his colleagues analyzed data from two open-label phase 1 trials (total of 37 patients) and three double-blind, placebo-controlled phase 2 trials (total of 255 patients). All men had CRPC with bone metastases. In these trials, patients experienced significant improvement in bone markers and decreases in PSA levels and pain. In one of the placebo-controlled trials, median overall survival was greater in the alpharadin groups compared with placebo recipients (65 vs. 46 weeks). The uptake of alpharadin into bone metastases occurs rapidly. In a separate analysis of data from a phase 1 pharmacokinetic and biodistribution study, the researchers found that alpharadin accumulates in bone metastases as early as 10 minutes from the time of injection. In addition, the drug exhibits minimal activity in the kidneys, liver, or other internal organs. Of the 292 patients in the phase 1 and 2 trials, fewer than 1% experienced CTC grade 4 hematological toxicity, about 4% experienced grade 3 anemia, and fewer than 3% of the patients experienced grade 3 platelets, neutrophils or white blood cells. The most common adverse events seen in all studies were nausea (33% of patients), bone pain (30%), fatigue (26%), diarrhea (26%), vomiting (20%), and constipation (20%). The researchers observed no signs of renal or hepatic toxicity. “This pharmaceutical has proven to be very, very safe,” Dr. Nilsson said. “It has a benign side effect profile. It gives very little toxicity to the bone marrow, which is the main risk organ in this disease. It is excreted in the bile and intestines so we don't see any toxic effects on the kidneys.” Researchers are evaluating alpharadin in a global phase 3, randomized, double-blind, multi-dose, placebo-controlled international clinical trial in men with CRPC with bone metastases. __________________ Mom's treatment history (link)