This article is from:Academic Horizon (ID: Global_Academia), header image from Visual China Group
The Tumor Is Not the Most Terrifying Aspect of Cancer; the Truly Lethal Weapon Is the Spread of Cancer Cells. For Cancer Patients, the Word “Metastasis” Brings the Profoundest Despair.
90% of cancer patients lose their lives due to malignant metastasis. To improve the survival rate of cancer patients, inhibiting the metastasis of cancer cells is undoubtedly of great significance. This is precisely the challenging problem that many scientific researchers are striving to address.
Paul Scherrer Institute（Paul Scherrer Institute）with the renowned Swiss-headquartered multinational pharmaceutical company Roche（Roche）A collaborative study has taken a significant step toward unraveling the malignant metastasis of certain common cancers. The research team focused on the lymphatic metastasis of cancer cells, deciphered for the first time the structure of a key signaling molecule, and on this basis screened for candidate drug molecules targeting it. These findings were recently published in the top academic journal Cell.
The lymphatic system is a major pathway for cancer cell dissemination. Similar to the circulatory system, the lymphatic system extends throughout the body, with lymphatic vessels interconnecting lymph nodes. The migration of cancer cells within this system is associated with signals received by cell surface receptors.
Signal transduction plays a crucial role in the biological world, where signals are transmitted not only between individuals but also between cells. In vertebrates, chemokines represent a common class of signaling proteins utilized by cells. There are more than 40 distinct chemokines, each of which binds specifically to particular chemokine receptors on the cell surface. Upon binding, cells elicit specific responses to the signal.
Image source: 123RF
Chemokine Receptor-7(abbreviated as CCR7)These are receptors that regulate cell motility. Upon binding to appropriate extracellular signaling proteins, they trigger intracellular cascades, directing cells to migrate toward the highest concentration of the signaling protein. Cells follow chemokines much like hounds tracking a scent.
Under normal circumstances, lymphocytes in the human immune system continuously migrate to lymph nodes via CCR7. However, cunning cancer cells can exploit CCR7 to meet their expansion needs. Signal proteins guide them away from the primary tumor into the lymphatic system, where they disseminate throughout the body and ultimately form metastatic tumors in other tissues.
▲ Cancer cells utilize CCR7 on the cell membrane to metastasize to lymph nodes (Image source: Reference [1])
For this very reason, scientists at PSI and Roche identified CCR7 as a potential target for intervening in the lymphatic spread of cancer cells. “The goal is to find the right molecule that prevents the signaling protein from binding to the receptor, thereby blocking signal transmission into the cancer cells,” said Dr. Steffen Brünle, co-first author.
However, to date, there are only a handful of small-molecule drugs targeting chemokine receptors on the market, and clinical trials of related agents have often failed due to suboptimal efficacy and selectivity. To overcome these obstacles, scientists sought insights from molecular structures, beginning with the elucidation of the three-dimensional structure of the CCR7 protein.
“The first challenge we encountered was producing the protein—specifically, generating a form amenable to analysis by X-ray crystallography,” explained Dr. Jörg Standfuss, one of the co-leads. To accelerate the research process, Roche developed a novel protein modification technology module and employed “crystallization chaperones” to determine the structure of the human CCR7 protein.
▲ CCR7 Receptor and the Intracellular Allosteric Antagonist Cmp2105 (Image source: Reference [1])
Information on the precise structure of the receptor has opened up a new avenue for the design of small-molecule drugs. The research team began searching for active compounds capable of serving as ligands that specifically bind to the intracellular site of CCR7. From Roche’s library of 2.3 million compounds, scientists employed computer simulations to first screen approximately 300 compounds based on 3D shape similarity. Subsequently, by assessing thermal stability, they identified five candidate compounds for further development as potential anticancer agents.
“The preliminary results are encouraging. ‘Our experiments demonstrate that the synthetic molecules bind to receptors within cells, thereby preventing the initiation of the intracellular signaling cascade responsible for cell migration,’ explained Dr. Brünle.”
▲ Five small-molecule ligands specifically binding to the allosteric pocket of CCR7 (Image source: Reference [1])
To the surprise of researchers, one active molecule identified in the screening, Navarixin, has already entered Phase II clinical trials as a potential anti-metastatic drug for colorectal cancer and other aggressive cancers. It was previously believed to bind to a different receptor, thereby inhibiting other functions of cancer cells. These findings, however, indicate that it is a multi-target antagonist, holding significant promise for overcoming resistance encountered with single-target therapies.
We look forward to the continued success of scientists’ research, hoping that new drugs to block the malignant metastasis of cancer cells will be developed soon, so that more patients can henceforth face cancer without fear of its deadliest threat.
References:
[1] K. Jaeger et al., (2019) Structural basis for allosteric ligand recognition in the human CC chemokine receptor 7. Cell. DOI: 10.1016/j.cell.2019.07.028
[2] Preventing tumour metastasis. Retrieved Aug. 25, 2019, from https://www.psi.ch/en/media/our-research/preventing-tumour-metastasis
This article is from:Academic Horizon (ID: Global_Academia)