Combination Tx targets both tumour cells and tumour blood vessels

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Each day, normal human cell tissues express a protein known as p53 that wages war against potential malignancies. However, between 30% and 40% of human breast cancers express a defective (mutant) form of p53 that helps cancer cells proliferate and grow. Now, researchers at the University of Missouri have found that combining a cancer therapy, which activates mutant p53 and is currently under a clinical trial, with a second drug therapy that helps suppress tumour blood vessels found in cancer cells, can help significantly reduce the spread of breast cancer tumours while also causing cancer cell death.

In a majority of breast cancer cases, a mutated p53 protein exists. Mutated p53 plays a key role in promoting tumour cells and helps in the development of blood vessels that supply oxygen and other nutrients the tumour needs to grow. However, a specific molecule known as APR-246, which is the drug currently under a human clinical trial, has the ability to restore p53 function giving the body the tools it needs to fight cancer.

“In order to effectively treat tumours, therapeutics are being developed that target mutant proteins that help grow cancer cells; APR-246 is one of those drugs,” said Salman Hyder, the Zalk endowed professor in tumour angiogenesis and professor of biomedical sciences in the MSU College of Veterinary Medicine and the Dalton Cardiovascular Research Centre. “However, we have identified another way to target cancer cells using APR-246 that attack breast tumour cells as well as antibodies that target the blood vessels that supply nutrients to tumours. Our lab tested whether a combination of APR-246 and helpful antibodies would control tumour development by simultaneously restoring p53 protein function and reducing the tumour blood vessels that supply cancer cells with nutrients.” Hyder and his team chose a specific antibody, 2aG4, which has the ability to destroy blood vessels and prevent future growth.

In the human cell lines that were in vitro, or outside the body, researchers saw that APR-246 induced a significant amount of tumour cell death. Then, the team tested the combination therapy with APR-246/2aG4 in mice that had cancerous tumours. Tumour growth was more effectively suppressed by the combination treatment than by either agent alone. In some cases, the therapy completely eliminated cancerous tumours.

Additionally, the researchers found that the combination therapy more effectively induced cancer cell death and dramatically reduced the density of blood vessels, which serve as a major route for metastasis.

“APR-246, the drug currently in human clinical trial, is showing very promising results,” Hyder said. “Based on our findings, we can show that breast tumour growth might effectively be controlled by simultaneously targeting the p53 protein and the blood vessels that supply cancer cells through a combination therapy.”

The early-stage results of this research are promising. If additional studies are successful within the next few years, these compounds may be tested in human clinical trials with the hope of developing new treatments for breast and other cancers.

This research highlights the power of translational precision medicine and the promise of the proposed Translational Precision Medicine Complex (TPMC) at the University of Missouri. The TPMC will bring together industry partners, multiple schools and colleges on campus, and the federal and state government to enable precision and personalized medicine. Scientific advancements made at MU will be effectively translated into new drugs, devices and treatments that deliver customised patient care based on an individual’s genes, environment and lifestyle, ultimately improving health and well-being of people.

Abstract
Background: Between 30 and 40% of human breast cancers express a defective tumor suppressor p53 gene. Wild-type p53 tumor suppressor protein promotes cell-cycle arrest and apoptosis and inhibits vascular endothelial growth factor–dependent angiogenesis, whereas mutant p53 protein (mtp53) lacks these functions, resulting in tumor cell survival and metastasis. Restoration of p53 function is therefore a promising drug-targeted strategy for combating mtp53-expressing breast cancer.
Methods: In this study, we sought to determine whether administration of APR-246, a small-molecule drug that restores p53 function, in combination with 2aG4, an antibody that targets phosphatidylserine residues on tumor blood vessels and disrupts tumor vasculature, effectively inhibits advanced hormone-dependent breast cancer tumor growth.
Results: APR-246 reduced cell viability in mtp53-expressing BT-474 and T47-D human breast cancer cells in vitro, and significantly induced apoptosis in a dose-dependent manner. However, APR-246 did not reduce cell viability in MCF-7 breast cancer cells, which express wild-type p53. We next examined APR-246’s anti-tumor effects in vivo using BT-474 and T47-D tumor xenografts established in female nude mice. Tumor-bearing mice were treated with APR-246 and/or 2aG4 and tumor volume followed over time. Tumor growth was more effectively suppressed by combination treatment than by either agent alone, and combination therapy completely eradicated some tumors. Immunohistochemistry analysis of tumor tissue sections demonstrated that combination therapy more effectively induced apoptosis and reduced cell proliferation in tumor xenografts than either agent alone. Importantly, combination therapy dramatically reduced the density of blood vessels, which serve as the major route for tumor metastasis, in tumor xenografts compared with either agent alone.
Conclusion: Based on our findings, we contend that breast tumor growth might effectively be controlled by simultaneous targeting of mtp53 protein and tumor blood vessels in mtp53-expressing cancers.

Authors
Yayun Liang, Benford Mafuvadze, Cynthia Besch-Williford, Salman M Hyder

University of Missouri-Columbia material
Breast Cancer – Targets and Therapy abstract


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