Propagermanium (already approved as a treatment for hepatitis)
https://aon.tokyo/propa/propa.pdf
https://aon.tokyo/propa/propa.pdf
January 3, 2007 Next Generation Cancer Research Seeds Strategic Development Program Tel: 03-3570-0404 (Secretariat) Kyushu University Tel: 092-802-2130 (Public Relations Office) Discovery of an existing drug that strongly inhibits cancer metastasis Fbxw7, an important protein involved in the formation of the cancer niche, has been found to inhibit CCL2. Fbxw7, an important protein involved in the formation of the cancer niche, inhibits CCL2. When Fbxw7 is decreased, CCL2 is increased and cancer metastasis is induced. CCL2 rises when Fbxw7 is decreased, resulting in an increase in cancer metastasis. The researchers succeeded in strongly inhibiting cancer metastasis by using propagermanium (an existing drug already in clinical use for the treatment of hepatitis), which inhibits the elevated CCL2. The company succeeded in strongly inhibiting cancer metastasis. As part of the Program for Strategic Development of Next-Generation Cancer Research Seeds (P-DIRECT), a research team led by Senior Professor Keiichi Nakayama at the Institute of Bioregulatory Medicine, Kyushu University, has identified a novel protein, Fbxw7Note1) , which is an important regulator of cancer niches. Fbxw7Note 2), an important protein that regulates the cancer nicheNote 1) , and found that the existing drug propagermaniumNote 3) ( 3) (CCL2 inhibitor), an existing drug, and succeeded in strongly inhibiting cancer metastasis.
It is known that a group of cells called "cancer niche" exists around cancer cells and actively helps cancer cells to proliferate and metastasize. In particular, blood-derived "fibroblasts" and "monocytes" are important components of cancer niches. In cancer therapy, it is necessary to eliminate not only cancer cells but also cancer niches at the same time. However, the mechanisms by which cancer niches are formed are not well understood. Fbxw7 is a molecule that has been found to be mutated in many cancers. Fbxw 7 levels are high in some people and low in others. The research team examined blood cells from breast cancer patients and found that those with low Fbxw7 expression were more likely to have their cancer recur. They also found that lowering the amount of Fbxw7 in mice (artificially destroying the geneNote 4), as is done in humans, makes the cancer more likely to metastasize. When Fbxw7 levels are low, fibroblasts in the cancer periphery produce a protein called "CCL2Note 5". CCL2Note 5), which abnormally attracts monocytesNote 6) around the cancer cells and creates a cancer niche. CCL2 is a protein that is secreted in excess from germinated cells. To inhibit the function of CCL2, we administered propagermanium, a CCL2 inhibitor, to mice. When propagermanium, a CCL2 inhibitor, was administered to mice to inhibit the function of CCL2, the accumulation of monocytes disappeared and the growth of cancer cells at the metastatic site was suppressed. Propagermanium is an existing drug that has already been used in humans for the treatment of hepatitis, and we plan to proceed with clinical trials of propagermanium at the earliest possible date. The results of this research were published on January 2, 2015 (EST) in the American scientific journal Journal of Clinical Investigation The results were published on January 2, 2015 (EST) in the U.S. scientific journal "Journal of Clinical Investigation. These results were obtained through the following projects, research areas, and research themes. Program for Strategic Development of Next-Generation Cancer Research Seeds (P-DIRECT) Research Area Program leader: Tetsuo Noda, Director, Cancer Institute, Cancer Research Institute, Japan) Title: "Development of Therapeutic Agents Targeting Ubiquitinating Enzymes that Regulate Cancer Growth" Principal investigator: Keiichi Nakayama, Professor, Institute of Bioregulatory Medicine, Kyushu University) P-DIRECT aims to develop new therapeutic agents targeting ubiquitinating enzymes that regulate cancer growth. P-DIRECT aims to establish a new research system that can efficiently and promptly develop the seeds of Japan's excellent basic research, which will lead to the next generation of cancer treatment, to a level where they can be passed on to pharmaceutical and medical device companies.
＜Cancer cells do not exist on their own, but are surrounded by many surrounding cells. Recently, it has become clear that these surrounding cells form a "cancer niche" that supports the survival and proliferation of cancer cells (Figure 1). Cancer niche cells help cancer cells proliferate and metastasize by secreting growth factors necessary for cancer cell growth and by reducing the function of immune cells that come to kill cancer cells. Therefore, it is expected that cancer therapy can inhibit cancer progression by simultaneously eliminating not only cancer cells but also "cancer niches. However, cancer research to date has focused mainly on the properties and mutations of cancer cells themselves, and not much is known about the mechanisms by which cancer niches are formed. Similarly, most of the anti-cancer drugs so far have acted on cancer cells to inhibit their proliferation, and there has been little development of anti-cancer drugs that work to eliminate cancer niches. Fbxw7 is a protein that has been well characterized in cancer cells and has been known to inhibit cell proliferation. The research team focused their analysis on the function of Fbxw7 in cancer niches. ＜First, the research team analyzed Fbxw7 in blood cells from breast cancer patients. The results showed that the amount of Fbxw7 in blood cells was high or low, depending on the individual. The research team first analyzed Fbxw7 in blood cells of breast cancer patients. There are three main types of breast cancer: hormone receptor-positive breast cancerNote 7), HER2-positive breast cancerNote 8), and triple-negative breast cancer (Note 9). Among patients with triple negative breast cancer, which is the most malignant type of breast cancer, less than 10% of those with high Fbxw7 recur, but 50% of those with low Fbxw7 recur. This is because the Fbxw7 level in blood cells is the highest in the triple-negative breast cancer group, and the Fbxw7 level is the lowest in this group. This result indicates that the prognosis of cancer patients can be predicted by measuring Fbxw7 levels in blood cells. Next, mice artificially deficient in Fbxw7 in blood cells (bone marrow cells) were created and transplanted with cancer cells. When malignant melanoma, lung cancer, and breast cancer cells were transplanted into mice, metastasis to the lung increased in all cancer cells (Fig. 3). In addition, Fbxw7-deficient mice died soon after transplantation of cancer cells (Fig. 4). In other words, the reduced Fbxw7 in bone marrow cells was the cause of the increased susceptibility to cancer metastasis, leading to a poor prognosis. Close examination of the lungs of these mice revealed that numerous bone marrow cells surrounded the cancer cells, forming a cancer niche. The niche is populated by many bone marrow cells, especially monocytes, which assist in the proliferation of cancer cells (Fig. 5). Furthermore, in mice lacking Fbxw7, a protein called "CCL2," which attracts monocytic cells, was found to be present. In addition, we found that Fbxw7-deficient mice express elevated levels of a protein called CCL2, which attracts monocytes. In other words, the reduction of Fbxw7 promotes the upregulation of CCL2 This indicates that the decrease in Fbxw7 promotes the increase in CCL2 and accelerates the formation of cancer niches. If CCL2 can be suppressed, the cancer niche can be expected to disappear. In order to suppress the effect of CCL2 upregulation, Fbxw 7-deficient mice were treated with propagermanium, a CCL2 inhibitor. As a result, monocytes did not accumulate at the site of cancer metastasis and the size of cancer cells at the metastatic site was significantly reduced (Fig. 6). In other words, the inhibition of cancer metastasis was successfully achieved by inhibiting CCL2 using existing drugs. These results indicate that Fbxw7 in the cancer niche cells suppresses cancer metastasis by regulating the amount of CCL2 These results indicate that Fbxw7 in cancer niche cells functions to inhibit metastasis of cancer cells by regulating the amount of CCL2. This research has clarified a part of the mechanism of cancer niche formation, and further progress in this research is expected in the future. ＜The development of new drugs has been declining in recent years due to their low success rate and the huge amount of money involved. The CCL2 inhibitor (propagermanium) used in this study has already been approved as a drug and has been used as an oral chronic hepatitis B treatment. In the future, we would like to proceed with clinical trials to see if this therapeutic agent actually has metastasis inhibitory effects on cancer patients.
＜Cancer cells are surrounded by many surrounding cells, forming a "cancer niche" that supports the survival and proliferation of cancer cells. Cancer niche cells that form cancer niches help cancer cells proliferate and metastasize by secreting growth factors necessary for cancer cell growth and by reducing the function of immune cells that come to kill cancer cells. Fig. 2 Amount of Fbxw7 in blood cells and disease-free survival rate It is known that some humans have high levels of Fbxw7 in their blood cells, while others have low levels. Low levels of Fbxw7 are associated with a higher risk of cancer recurrence (left panel). Among patients with high-grade breast cancer called triple negative, those with high Fbxw7 have less than 10% chance of recurrence, while those with low Fbxw7 have 50% chance of recurrence. However, those with low Fbxw7 have a 50% chance of recurrence (Fig. right).
Figure 3: Artificial Fbxw7-deficient mice are prone to metastasis Melanoma cells (left), lung cancer cells (center), and breast cancer cells (right) were transplanted into mice artificially deficient in Fbxw7. In the Fbxw7 artificially-deficient mice, many cancer cells of all cancer types metastasized to the lungs.
Fig. 4 Fbxw7 artificial deficient mice are prone to early death after cancer transplantation Melanoma cells were transplanted into mice artificially deficient in Fbxw7. Fbxw7 artificially deficient mice die early after cancer transplantation. Figure 5: Fbxw7 artificially deficient mice have an increased cancer niche In mice artificially deficient in Fbxw7, breast cancer cells metastasized to the lungs (red) are surrounded by a large number of bone marrow cells (green), forming a cancer niche. Figure 6.
Fig. 6 CCL2 inhibitor (propagermanium) suppresses cancer metastasis. Melanoma cells (left) or breast cancer cells (right) were transplanted into mice artificially deficient in Fbxw7. When these mice were treated with a CCL2 inhibitor (propagermanium), the growth of metastasized cancer was strongly inhibited in both cancers.
＜(Note 1) Cancer niche: A group of cells surrounding cancer cells. It assists the proliferation and metastasis of cancer cells by acting on them in various ways. Fbxw7 is a protein known to suppress cell proliferation. The research group discovered a new function of Fbxw7 in suppressing CCL2. CCL2. Propagermanium is an existing drug that inhibits CCL2, and is the only organogermanium preparation approved as a pharmaceutical product. Until now, it has been used as an oral treatment for chronic hepatitis B. (Note 4) Mice in which Fbxw7 is artificially destroyed Mice in which the target gene is destroyed or deleted by genetic manipulation so that it no longer works. This is a mouse in which the target gene is disrupted or deleted by manipulating the gene so that it no longer works. In this study, we used mice in which the Fbxw7 gene was artificially deleted in bone marrow cells. CCL2 is a protein called "chemokine" that has the ability to collect monocytes, one of the bone marrow cells. Monocyte cells are one of the cells produced from bone marrow. In cancer niches, they have functions such as creating new blood vessels and reducing the function of immune cells that come to kill cancer cells. Among the subtypes of breast cancer, those with hormone receptors. Since it feeds on female hormones to grow, hormone therapy is used to create an environment in which the cancer cells cannot receive hormone stimulation. The prognosis is relatively good. Among the subtypes of breast cancer, those with the HER2 protein are the most common. Treatment is based on the drug Herceptin, which blocks the growth stimulation of HER2. The prognosis is relatively good. A subtype of breast cancer that has neither hormone receptors nor HER2. Currently, there is no established treatment.
＜F-box protein Fbxw7 inhibits cancer metastasis in a non-cell-autonomous manner. Fbxw7 inhibits cancer metastasis in a non-cell-autonomous manner" (F-box protein Fbxw7 inhibits cancer metastasis in a non-cell-autonomous manner) ＜Contact ＞ ＜Research ＞ Keiichi Nakayama Department of Molecular Medical Science, Institute for Biomedical Research, Kyushu University, 3-1-1 Umade, Higashi-ku, Fukuoka 812-8582, Japan Tel: +81-92-642-6815 Fax: +81-92-642-6819 E-mail: nakayak1@bioreg.kyushu-u.ac.jp Motoharu Seiki, Group Leader, Innovative Cancer Medical Seeds Development Group, P-DIRECT P-DIRECT Secretariat, Cancer Institute, The Cancer Institute of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan Tel: 03-3570-0404 Fax: 03-3570-0436 E-mail: jisedaigan.admin@jfcr.or.jp http://p-direct.mext.go.jp/
■ An existing drug for the treatment of heart failure that suppresses the metastasis of cancer.
Atrial natriuretic peptide (ANP) ( a hormone secreted by the heart and approved as an existing drug.)
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http://neovisionconsulting.blogspot.jp/2017/10/blog-post_65.html
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