- New treatment and target for cancer. Prostate or breast cancer kills when cancerous cells invade vital organs like the brain or lungs. A curative approach, designed to attack a patient’s unique cancer, is needed to improve patient survival. To this end, we discovered a new anti-cancer agent called CT20p. CT20p is a small peptide formed by 20 amino acids, which are biological building blocks. CT20p prevents a cancer cell from attaching to tissues and, as a result, cancer cells lose needed survival signals and die. To understand how CT20p works, we found that the peptide specifically inhibits a protein called called chaperonin-containing-TCP1 or CCT, which is basically a helper protein that shapes other proteins into their final three-dimensional forms. Without CCT, a cancer cell cannot produce the components that it needs to move, grow and survive. Importantly, we found that cancers cells made more CCT than normal cells, and patients whose tumors contain large amounts of CCT, died more quickly. These findings suggest that inhibiting CCT with CT20p is an effective therapeutic approach that could improve the survival of cancer patients whose tumors contain CCT. The aims of our project are, first, to learn how CCT helps prostate and breast cells become cancerous, and, second, to discover how CT20p binds and inhibits the activity of CCT to develop a screening assay that will help us find new CCT inhibitors. By completing the work proposed, we will produce a novel therapeutic designed to inhibit the invasive nature of breast and prostate cancer with minimal side effects.
- New immunotherapy approach. Women (and men) are diagnosed with breast cancer every day. While cancer that is localized to the breast is survivable, when the cancer recurs or spreads to other vital organs, like the lungs or brain, conventional treatments are ineffective. In order to reduce death due to breast cancer, new treatments that prevent cancer recurrence and dissemination (metastasis) through the body are needed. One promising approach is to harness the ability of the immune system to recognize and eliminate cancerous cells. The immune system is an important part of the body’s defenses against infections that can also be used to fight cancer. Some types of cancers are visible to the immune system and therapies can be designed to stimulate anti-cancer defense mechanisms. However, other cancers, like breast cancer, avoid detection by the immune system and are able to subvert normal immune protection to support cancer growth and spread. New therapies that restore the powerful immune responses to prevent breast cancer recurrence and eliminate metastasis could save patient lives. Immunotherapy involves isolating and expanding immune cells, often from the patient’s own blood as active agents to eliminate cancer cells. One type of immune cell that is an effective killer of cancer cells is called a natural killer (NK) cell. Immunotherapy that activates NK cells would be a way to stop cancer growth. The problem is that immunotherapy is most effective when cancers are small, not when tumors are large or have spread. We propose to overcome this by combining immunotherapy with the killing action of CT20p, a novel peptide discovered by our lab. CT20p kills cells through the inhibition of a protein, called a chaperonin-containing-TCP1 or CCT, that is essential for folding proteins into their three-dimensional functional shapes. By inhibiting the chaperone, CT20p causes cell stress that kills breast cancer cells but also causes the dying cancer cells to emit signals that activate other immune cells like macrophages or NK cells to promote anti-tumor immunity. Anti-tumor immune cells can then kill cancer cells that escaped the initial treatment and moved through the body. Our studies focus on developing this double-pronged approach that could prevent cancer recurrence and spread.
- Using nanotechnology to deliver a therapeutic peptide. Death due to prostate or breast cancer occurs when the disease spreads to vital organs like the lungs or brain. Cancers that invades other organs cannot be cured, and patients with this complication may die within 5 years. Treatments for prostate or breast cancer, such as chemotherapy and radiation, can also cause serious side effects, such as nausea and vomiting or lowered resistance to infections. To help men and women with life-threatening forms of cancer, new targeted agents are needed that deliver toxic drugs to the cancer cells, without damaging normal, healthy cells. One promising approach is to load cancer drugs into ultrafine particles or nanoparticles that can carry drugs safely through the body, delivering their drug cargo to tumors. The problem is that sometimes nanoparticles accumulate in other organs, like the liver, and fewer drugs are then delivered to tumors. One way to solve this problem is to “address” the nanoparticles by adding a molecule on their surface that only binds to cancer cells. In this project, we are developing nanoparticles that localize to prostate and breast cancer cells dependent on an important nutrient called folate. Cancer cells need folate to power their metabolism and may take up nanoparticles coated with folate more readily than normal cells. By delivering drugs to breast tumors using folate-nanoparticles, we should increase the amount of drug that reaches tumors, while decreasing uptake by healthy tissues. This work will yield a new drug delivery agent that could extend the life expectancy of breast cancer patients, while minimizing side effects.
Breast Cancer Research Foundation (BCRF) grant 2015-2018 (renewed annually)
Title: Development of a Cytoskeletal-Disrupting Approach for the Treatment of Metastatic Breast Cancer
RO1EB019288 Grant 2014-2018
Title: A novel polymeric nanotechnology platform with imaging capabilities for targeted delivery of a therapeutic peptide
Role: MPI (with J. Manuel Perez)
Source: NIBIB, NIH