Development a new therapy approach for cancer bone metastasis
Development a new therapy approach for cancer bone metastasis, aimed at inhibiting a biochemical reactions responsible for metastasis due to breast cancer and prostate cancer.
The majority of breast cancer patients with bone metastases exhibit primarily osteophytic (bone destructive) lesions (80%–90%), although a small percentage (10%–20%) of patients exhibit primarily osteoblastic (bone building) lesions . Breast cancer cells secrete soluble factors that act on osteoblasts or osteoclasts to ultimately stimulate osteoclast cell differentiation in lytic lesions. The osteoclasts then degrade the bone, which releases stored growth factors that stimulate breast cancer cell proliferation. The weakening of bone at the sites of metastasis puts the patients at risk of severe bone pain, bone breakage, spinal compression and hypercalcemia that result in pain and death 
Metastasis accounts for more than 90% mortality in cancer patients (Breast cancer metastasis to bone: it is not all about PTHrP.)
First Stage. Development a new therapy approach for cancer bone metastasis
The first stage involves the creation of a database of participating proteins. An active centers of this proteins corresponding to highly selective inhibitors.
Second Stage. Development a new therapy approach for cancer bone metastasis
The second stage will directly performed in the laboratory. A series of in vitro verification experiments, on cell lines, all phases of preclinical studies will carty out in lab.
Start of Preparatory phase: As funds become available
The level of significance and scientific novelty of the study a new therapy approach for cancer bone metastasis
In this project, a multidisciplinary inhibition of the development of bone metastases resulting from breast cancer (BC) will be developed for the first time. This project will offer a comprehensive approach to inhibit key molecules in two biochemical processes leading to metastasis to bone tissue due to the development of breast cancer.
Inhibitors will be developed on the basis of natural peptides and imunoglobulins that will bind in the active center of selected key proteins, whose active participation in pathological processes leads to metastasis.
Inhibition of such key participants will be important in blocking of process of metastasis in two biochemical processes: metastasis of cancer cells into bone tissue and the development of bone disorders due to disruption of biochemical processes in the bones due to metastasis of cells from breast cancer in them.
The following proteins are subject for inhibition: Matrix metalloproteinase 2 (MMP2), Matrix metalloproteinase 9 (MMP9), chemokine receptor, product of the CXCR4 gene and chemokine CXCL12, Src kinase, transforming growth factor beta (TGF-beta) and its receptor core factor receptor, cap receptor receptor β (RANK), its ligand (RANKL).
Expected Results and Their Importance a new therapy approach for cancer bone metastasis
The result of the completed project will be the development of ten groups of inhibitors, characterized by high selectivity to the selected proteins, and the development of selective inhibitors directly to ten therapeutic targets will increase the effectiveness of therapy on the one hand and reduce adverse side effects on the other. The developed therapeutic approach will allow to stop the selected biochemical processes during metastasis and thereby significantly slow down / stop the development of metastases in bone tissue.
The developed therapeutic integrated approach will open a whole direction in targeted therapy of breast cancer and its accompanying bone metastasis.
Goals and objectives of the project development a new therapy approach for cancer bone metastasis
The aim of the project is to develop a targeted multidisciplinary therapeutic approach aimed at inhibiting various control points of biochemical reactions responsible for metastasis and development of bone disorders due to disruption of biochemical processes in the bones. As a result of the developed targeted therapy, ten classes of inhibitors will be developed for the following proteins: matrix metalloproteinase 9 (MMP9) and -2 (MMP2), chemokine receptor, CXCR4 gene product and chemokine CXCL12, Src kinase, transforming growth factor beta (TGF-beta) and its receptor, the receptor activator of the nuclear factor Kappa-β (RANK) and its ligand (RANKL), a protein associated with parathyroid hormone (PTHRP)
We suggest using the biophysical concept that we developed for the synthesis of new drugs. The concept is based on a method that includes steps to significantly reduce the number of “failed drugs” due to:
- Increasing the selectivity of the drug to the target protein
- Significant reduction in toxicity of the drug.
- Quick and effective subsequent removal of the drug from the patient.
Based on the biophysical approaches that we developed, highly selective peptides will be selected that will bind to the active center of target proteins and inhibit them, blocking further signal transmission.
The synthesized peptides will be divided by function and affinity for different groups of proteins:
- metalloproteinase 9 (MMP9) and -2 (MMP2),
- chemokine receptor, CXCR4 gene product and chemokine CXCL12,
- Src kinase,
- transforming growth factor beta (TGF-beta) and its receptor,
- Kappa-β nuclear factor activator receptor (RANK), its ligand (RANKL).
- Parathyroid Hormone Protein (PTHRP)
Proteins and peptides have a number of properties that make them highly effective as therapeutic agents.
These include very precise specificity, high binding affinity, low toxicity and low risk of drug interactions. Their diversity also provides a very broad coverage of disease goals. Despite this, a relatively small number of peptide preparations are approved — about 60, because peptides, as a rule, have low bioavailability. Nevertheless, in recent years, methods have appeared that increase the stability and bioavailability of peptide drugs, such as the use of D-amino acids, the use of peptides penetrating the cell membrane (cell penetrating peptides), the use of adjuvant therapy, followed by recognition of peptides by human immune cells, which opens up a new century in the development of a new class of peptide therapeutic drugs. And currently, the number of peptide drugs is growing rapidly among drug candidates
One of the focus areas of modern pharmaceutical developments is breast cancer, which is the most common cancer in women, it accounts for 16% of all female oncological diseases. The incidence of breast cancer increases with age and is expected to increase due to an increase in life expectancy. Despite treatment success, metastases remain the leading cause of death in cancer patients, accounting for 90% mortality from solid tumors [Reciprocal modulation of mesenchymal stem cells and tumor cells promotes lung cancer metastasis]
Bone damage in cancer patients is mainly represented by either a metastatic lesion or osteoporosis, which can occur against the background of specific antitumor therapy. In the second case, the term CTIBL is used (cancer treatment — induced bone loss — reduction in bone mass due to antitumor treatment). Bone metastases have up to 1.5 million people in the world, and up to 500 thousand die from them each year [USE OF OSTEOMODIFICATING AGENTS FOR PREVENTION AND TREATMENT OF BONE TISSUE TREATMENT IN MALIGNANT NORMOUS FORMATIONS]. Most often, bones are affected by such common tumors as breast cancer (breast cancer) and prostate cancer (PCa) — up to 75%, non-small cell lung cancer (NSCLC) — up to 40%, as well as cancer of the thyroid gland, bladder, kidney non-Hodgkin’s lymphomas and multiple myeloma (MN).
Only bone metastases develop in 17–37% of women with metastatic disease. Bone metastases not only negatively affect the patient’s quality of life, but also reduces overall survival.
And post-mortem examination of approximately 70% of all patients dying of breast cancer have signs of metastatic bone disease, which many patients have a chronic condition (Clinical features of metastatic bone disease and risk of skeletal morbidity.)
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2.Kingsley, L.A.; Fournier, P.G.; Chirgwin, J.M.; Guise, T.A. Molecular biology of bone metastasis. Mol. Cancer Ther. 2007, 6, 2609–2617