Targeted Therapy Combined with Immune Modulation Using Gold Nanoparticles for Treating Metastatic Colorectal Cancer
Abstract
Topic Area: Colorectal cancer. Military Relevance Focus Area: Gap in cancer treatment. The second leading cause of cancer death for military members, Veterans, and their beneficiaries is colorectal cancer. Our proposal addresses a major gap in the ability to effectively treat these patients with advanced stage colorectal cancer. Our objective is to develop an effective treatment for metastatic colorectal cancer. Even with the advanced state of cancer care in the United States, almost 90% of patients with advanced stage colorectal cancer will die from their disease within 5 years. Current treatment options for these patients are surgery, if possible, radiation, and/or treatment with chemotherapy drugs designed to attack dividing cells. Unfortunately, advanced stage disease is often too widespread to be removed surgically, and the current arsenals of radiation and chemotherapy drugs are ineffective. Two promising alternatives to the current standard of care are to use newer "targeted" drugs that only kill cancer cells and to harness the power of the patient s immune system to attack their own cancer. Unfortunately, these two alternative approaches have not yet been successful in clinical trials for advanced stage colorectal cancer. We propose to develop a highly innovative, novel approach to treat metastatic colorectal cancer using gold nanoparticles coated with "targeted" agents that simultaneously block cancer-driving proteins and activate the patient s immune system to attack the patient s own cancer. Gold nanoparticles are extremely tiny balls of gold (13 nanometers in diameter) that can be coated with targeted agents. Due to the unique biology of tumors, gold nanoparticles injected in the blood will preferentially travel to tumors and be engulfed by tumor cells. This occurs because tumors recruit new blood vessels to feed the tumors cells and these blood vessels are much more "leaky" than normal blood vessels, which means the gold nanoparticles congregate at the site of the tumor. New advances in gold nanoparticle chemistry also allow us to engineer the attachment of the targeted agents such that the agents are released from the gold nanoparticles only when the particle is engulfed by a cancer cell and not by normal cells. We propose to make gold nanoparticles coated with three different targeted agents. The first agent is designed to reduce the levels of a cancer-driving protein called MYC. In previous work, we have demonstrated that another molecule, PVT1, maintains the high levels of MYC in the cancer cell that allow the cells to grow and spread. We will design a molecule called a small-interfering RNA (siRNA) that can destroy PVT1. We will attach this siRNA targeting PVT1 to the gold nanoparticles. The second agent is designed to reduce the cancer s ability to shut off the patient s immune system. Cancer cells express certain molecules that protect them from being attacked by the immune system. To block this ability, we will design another siRNA that targets one of these immune-disabling molecules, called PDL1. The third agent is designed to directly activate the patient s immune system. To do this, we will take advantage of the fact that the majority of humans have developed immunity to common diseases like the flu and measles, either through childhood vaccinations or from having the disease. The third agent is called a peptide antigen. It is basically a small piece of protein that was originally present in the virus that caused the flu or measles. This peptide antigen will be attached to the gold nanoparticle. When it is released inside of the cancer cell, the patient s immune system will be tricked into thinking that the cell is infected with the flu or measles and the patient s immune system will become activated and attack the cancer cell. With this three-pronged approach, we will be able to simultaneously reduce an important cancer-driver (MYC), block the ability of the can
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610427
Entities
People
- Branden Moriarity
Organizations
- United States Army
- University of Minnesota