Preclinical Development of Novel Parathyroid Hormone-Related Peptide Antagonist for Breast Cancer
Abstract
Overarching Challenge: To design new treatments to prevent breast cancer from spreading to bone. Background: Breast cancer is a deadly tumor because it can enter the bloodstream and spread (metastasize) throughout the body, including to the bone. When breast cancer spreads to bone, it can cause pain, fractures, and makes the cancer harder to treat, ultimately causing the patient to die from the disease. When breast cancer cells reach the bone, they make a factor called parathyroid hormone-related peptide (PTHrP), which turns on cells in the bone that erode the bone away. This creates a cavity for the cancer cells to grow in and also releases factors from the bone that help the cancer grow faster. Cancer cells growing in the bone are hard to treat with chemotherapy because the drugs don t reach the tumor cells. Instead, patients receive drugs called bisphosphonates or denosumab to try to keep the bone from eroding away, but these drugs aren t powerful enough and can only slow the process temporarily. The best way to treat the problem would be to block the PTHrP, but drugs that can do this don t concentrate in the bone enough to be effective and are toxic to the rest of the body. We have invented a way to bring the PTHrP-blocking drugs to the bone and keep them there. We attached the drugs to another protein that binds to collagen, which is abundant in bone. This causes the PTHrP-blocking drugs to be concentrated in the bone, and thus protects the bone from the invading tumor cells. We tested one of these PTHrP-blocking drugs in mice with breast cancer cells injected into their bones and found that they slow the growth of the cancer cells and prevent the erosion of the bones. Hypothesis: We hypothesize that PTHrP-blocking drugs that attach to bone collagen will stop breast cancer bone metastases from growing and will stop the thinning of the bones that is induced by breast cancer. Specific Aims: This study will be conducted in two aims. Aim 1 will compare the effectiveness of two different PTHrP-blocking drugs that attach to bone collagen, PTH(7-33)-CBD and PTH([-1]-33)-CBD, in preventing breast cancer cells injected into the bone marrow cavity from eroding through the bone cortex in mice. In Aim 2, we will use injection of breast tumor cells into the hearts of mice (intracardiac) to determine if our PTHrP-blocking drugs can prevent breast cancer from spreading from the bloodstream to the bone. Study Design: In Aim 1, we will compare two versions of our bone-targeted PTHrP-blocking drugs, PTH(7-33)-CBD and PTH([-1]-33)-CBD, to see which version of the drug works better in a mouse model of breast cancer bone metastases. We will inject breast cancer cells directly into the marrow cavity of the bone. Normally these cells will grow and erode through the bone cortex. However, the bone-targeted PTHrP-blocking drugs can prevent this from happening. We will compare the two different versions of the drug and compare different doses to see which drug is most effective. We will also perform separate studies to test how the two drugs are metabolized and whether they cause any toxic effects in the rest of the body to make sure they are safe before testing them in people. We will also test the drugs in cell culture systems to better understand exactly how they work. In Aim 2, we will again test same PTHrP-blocking drugs in mice, but this time we will inject the breast cancer cells directly into the heart rather than injecting them into the bone marrow, and we will test if the drugs can prevent the cells from spreading to the bone and growing there. This is a harder experiment to perform, but it tells more directly if the drugs can keep cancer cells from spreading to bone in the same way they do in breast cancer patients. Impact: A positive result in either or both aims will be a tremendous achievement. These experiments will provide critical data needed to advance these drugs into clinical trials wi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610020
Entities
People
- Robert Gensure
Organizations
- Tufts Medical Center
- United States Army