Breast Cancer

Overview

One in 8 women will develop invasive breast cancer over the course of her lifetime. In 2014, an estimated 232,670 new cases of invasive breast cancer were diagnosed in the U.S., along with 62,570 new cases of non-invasive (in situ) breast cancer. For women in the United States, breast cancer death rates are second highest behind lung cancer resulting in 40,000 deaths in 2014. Fortunately, death rates have been decreasing since 1989, with larger decreases being seen in women under 50. These decreases are thought to be the result of treatment advances, earlier detection through screening, and increased awareness.

About 85% of breast cancer occurs in women who have no family history of the disease. These occur due to genetic mutations acquired through life, rather than inherited mutations. Chemotherapy and radiation have long been the standard, aggressive treatments for breast cancer and other types of cancer. Apart from having severe side effects, these treatments are not always wholly effective, as breast cancer can come out of remission.

Progress Toward a Cure

With support from California’s stem cell agency, the California Institute for Regenerative Medicine (CIRM), breast cancer researchers have made a groundbreaking discovery by developing a cell therapy using a single antibody, which has been shown to kill dozens of different types of cancerous cells, including those that cause breast cancer.

These developments are based on research that began a decade ago at Stanford School of Medicine, where researchers discovered a link between cancer cells and high levels of a protein called CD47 while studying leukemia. Dr. Irving Weissman, the stem cell biologist behind the breakthrough, found a CD47-blocking antibody that could cure some cases of leukemia by stimulating the immune system to recognize cancer cells as invaders. [1] More recently, Weissman has established a link between CD47 and all types of cancerous cells, including solid tumors. Cancer cells have higher levels of CD47 than healthy cells—creating a “don’t eat me” signal to the immune system. This signal essentially cloaks the cancer cells from being identified and removed by the immune system. The inordinate amounts of CD47 produced by the cancer cells effectively trick the immune system into leaving the cancer cells intact.

“What we’ve shown is that CD47 isn’t just important on leukemias and lymphomas,” Weissman told Science magazine. “It’s on every single human primary tumor that we tested.” Weissman and his team used that observation to develop an antibody that blocks the CD47 signal, thereby masking the “don’t eat me” signal. This causes the immune system to attack the cancerous cells.

In tests on laboratory mice infected with a litany of human cancers—breast, ovarian, colon, bladder, brain, liver, prostate, and others—the antibody was effective in leading to death of the cancerous cells. “We showed that even after the tumor has taken hold, the antibody can either cure the tumor or slow its growth and prevent metastasis,” said Weissman.

Weissman is now moving forward with a Phase 1/2a human clinical trial at Stanford University to test the safety and effectiveness of the CD-47 antibody therapy in solid tumors. [2] Dr. Weissman is hoping that this work will have implications for all types of cancer.

In another arm of research, Dr. Weissman is also working on a cell replacement therapy specifically focused on metastatic breast cancer. This approach would serve as a form of immunotherapy where the patient’s blood stem cells are removed, purified, then reinjected. Many years ago, Dr. Weissman, along with Dr. Judith Shizuru, Dr. Robert Negrin, and the late Dr. Karl Blume, performed a small-scale clinical trial that showed significant survival for women who were treated with their own modified blood stem cells. After loss of funding for the initial trial, Dr. Weissman and his team are taking up the mantle again with hopes to have several options for breast cancer patients.

Selected disease and research progress information provided by the California’s stem cell research funding agency, the California Institute for Regenerative Medicine (CIRM). Visit www.cirm.ca.gov for more updates.

Relevant Materials:

1. Weissman, Irv. “Clinical Investigation of a Humanized Anti-CD47 Antibody in Targeting Cancer Stem Cells in Hematologic Malignancies and Solid Tumors.” CIRM Disease Team Therapy Development III Summary. California Institute for Regenerative Medicine. https://www.cirm.ca.gov/our-progress/awards/clinical-investigation-humanized-anti-cd47-antibody-targeting-cancer-stem-cells

2. “HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype.” Gilbert PM, Mouw JK, Unger MA, Lakins JN, Gbegnon MK, Clemmer VB, Benezra M, Licht JD, Boudreau NJ, Tsai KK, Welm AL, Feldman MD, Weber BL,Weaver VM. J Clin Invest. 2010 May;120(5):1535-50. doi: 10.1172/JCI39534. Epub 2010 Apr 12. http://www.ncbi.nlm.nih.gov/pubmed/20389018

3. “The Prognostic Role of a Gene Signature from Tumorigenic Breast-Cancer Cells.” Rui Liu, Ph.D., Xinhao Wang, Ph.D., Grace Y. Chen, M.D., Ph.D., Piero Dalerba, M.D., Austin Gurney, Ph.D., Timothy Hoey, Ph.D., Gavin Sherlock, Ph.D., John Lewicki, Ph.D., Kerby Shedden, Ph.D., and Michael F. Clarke, M.D. N Engl J Med 2007; 356:217-226January 18, 2007DOI: 10.1056/NEJMoa063994. http://www.nejm.org/doi/full/10.1056/NEJMoa063994#t=abstract

4. “The road to purified hematopoietic stem cell transplants is paved with antibodies.” Weissman I., J. Shizuru, A. Logan. Curr Opin Immunol. 2012 Oct;24(5):640-8. doi: 10.1016/j.coi.2012.08.002. Epub 2012 Aug 29. http://www.ncbi.nlm.nih.gov/pubmed/22939368

5. “Human neural stem cell tropism to metastatic breast cancer.” Zhao D, Najbauer J, Annala AJ, Garcia E, Metz MZ, Gutova M, Polewski MD, Gilchrist M, Glackin CA, Kim SU, Aboody KS. Stem Cells. 2012 Feb;30(2):314-25. doi: 10.1002/stem.784.http://www.ncbi.nlm.nih.gov/pubmed/22084033

6. Holden, Anne. “Breast Cancer Tumors Recruit Immune Cells to the Dark Side.” 30 March 2015. California Institute for Regenerative Medicine. http://blog.cirm.ca.gov/2015/03/30/breast-cancer-tumors-recruit-immune-cells-to-the-dark-side/

7. Weissman, Irv. “CIRM Stem Cell #SciencePitch.” 19 March 2013. California Institute for Regenerative Medicine. https://www.youtube.com/watch?v=dVqO62APPSU

Footnotes

[1] “Phase 1 Safety Assessment of CPCB-RPE1, hESC-derived RPE Cell Coated Parylene Membrane Implants, in Patients with Advanced Dry Age Related Macular Degeneration.”  California Institute for Regenerative Medicine.  https://www.cirm.ca.gov/our-progress/awards/phase-1-safety-assessment-cpcb-rpe1-hesc-derived-rpe-cell-coated-parylene

[2] “Clinical Investigation of a Humanized Anti-CD47 Antibody in Targeting Cancer Stem Cells in Hematologic Malignancies and Solid Tumors.”  CIRM Disease Team Therapy Development III Grant Summary.  California Institute for Regenerative Medicine.  https://www.cirm.ca.gov/our-progress/awards/clinical-investigation-humanized-anti-cd47-antibody-targeting-cancer-stem-cells.”

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