Targeting Multifaceted Proteins Can Restore Drug Sensitivity in Breast Cancer Patients

Designed to Cure

Scientists are exploring alternative treatments for breast cancer tumors that have become resistant to existing drugs. Image Credit: Flickr user Gerry Lauzon

It’s an all too common problem: A patient’s tumor cells develop resistance to standard drug therapies and oncologists are left with no alternative treatment options. This is often the case for ER-positive breast cancer. Initially, the tumor cells may be responsive to tamoxifen or Faslodex, which block estrogen receptors in order to limit the physiological effects of the hormone. Over time, however, tumor cells can develop resistance to these drugs, and they become less effective for preventing cell growth and proliferation.

Recently, scientists identified a way to restore drug sensitivity to these cancer cells. It was previously known that the protein GRP78 is elevated in ER-positive breast cancer tumors, and scientists demonstrated that it is possible reduce levels by using a phosphorodiamidate morpholino oligomer to modify the expression of the HSPA5 gene, which codes for GRP78. Given this treatment, previously resistant tumor cells responded to tamoxifen. In October 2016, scientists at Wake Forest Baptist Medical Center demonstrated the effectiveness of this therapeutic strategy in animal models.1

Interestingly, lowering levels of GRP78 also increased cellular levels of essential fatty acids, such as linoleic acid, so the second part of the study involved treating mice with increasing doses of linoleic acid and comparing the effects to those of the morpholino treatment. They found that the two strategies have the same effect, which demonstrates that fatty acid regulation plays a critical role in cancer. Now, the research group is exploring the role of diet in breast cancer treatment outcomes, since linoleic acid is common in many foods, including  flaxseed, soybeans, tofu and walnuts, and it is also included in omega-3 dietary supplements.2

This extensive study has multiple implications for biomedical research. First, by revealing the role of GRP78 in both cancer cell proliferation and metabolic regulation, it highlights the importance of exploring multiple aspects of protein function in order to identify new disease treatments co4lasl. Also, it demonstrates the growing significance of morpholinos in biologics research. For life science companies looking to direct their research in either of these areas, there are software solutions that can support efforts.

Delving More Deeply Into Disease-Associated Proteins

By exploring the additional cellular functions of target proteins, scientists may be able to expand possible disease treatments. The paper from the Wake Forest study group showed that GRP78 levels are associated with both estrogen sensitivity and intracellular polyunsaturated fat levels, suggesting that there are multiple routes through which tamoxifen resistance may be overcome. This could be the case for other diseases that elude treatment by developing resistance to the first-line therapy. By identifying new ways to target a disease-associated protein, scientists may find replacement therapies to use when one therapy stops working for a patient.   

This exploratory research will likely require scientists to generate and analyze large amounts of data about particular proteins in order to be successful. Modern software that supports data analysis and integration is making broad research like this feasible for the first time. By improving the quality and efficiency of data processing, scientists can identify possible candidates more quickly and direct their research efforts toward only the most promising leads.

When a research group uncovers new ways in which a particular protein contributes to cell function or disease progression, it is important that the information be shared across the organization, as it may be relevant to the efforts of other scientists and research groups. For instance, since GRP78 seems to play a role in both endocrine and metabolic function, as well as cancer progression, the new study may be relevant for researchers who are working on treatments for conditions related to any of those fields. Software that enables intraorganizational collaboration ensures that all researchers have access to information that can support their research, leading to a strong foundation of organizational knowledge that will increase the company’s capacity for innovation.

Exploring the Use of Morpholinos in Disease Treatment

Another important aspect of the Wake Forest group’s study is that it signifies a growing trend toward the use of different types of biologics for disease treatment, such as morpholinos. Unlike monoclonal antibodies, which bind directly to their target proteins, phosphorodiamidate morpholino oligomers bind to DNA in order to regulate the transcription of a particular gene. The result is an increase or decrease in the levels of the protein for which the gene codes.

This strategy may be relevant for a wide range of diseases. Although it has had limited success so far, with a proposed treatment for Duchenne’s muscular dystrophy ending in clinical trials,3  morpholinos are currently being studied for the treatment of prostate cancer,4 and the Wake Forest study highlights their promise for tamoxifen-resistant breast cancer treatment. No matter what disease is being studied, biologics researchers considering morpholino-based treatments can use modern screening software to identify the most promising candidates for research and development.

Overall, while the recent study on the multiple roles of GRP78 in breast cancer cells reveals important insights for researchers trying to treat the disease itself, the findings also have implications for future research into other diseases. Based on the study, it is clear that disease researchers may be able to facilitate better patient outcomes by taking advantage of the multiple cellular functions of particular proteins when developing disease treatment strategies.

BIOVIA Designed to Cure is an advanced industry solution experience that promotes knowledge-based innovation by supporting high-level data analytics and facilitating collaboration across a life science organization.  In particular, Designed to Cure for Biologics additionally supports the identification, design and optimization of possible drug candidates like morpholinos. Contact us today for more information about our unique software offerings.

  1. “Endoplasmic Reticulum Stress Protein GRP78 Modulates Lipid Metabolism to Control Drug Sensitivity and Antitumor Immunity in Breast Cancer,” October 1, 2016, http://cancerres.aacrjournals.org/content/76/19/5657
  2. “Scientists identify protein involvement in restoring effectiveness of common treatment for breast cancer,” October 3, 2016, https://www.sciencedaily.com/releases/2016/10/161003093410.htm
  3. “What Can We Learn From Clinical Trials of Exon Skipping for DMD?” March 11, 2014, http://www.nature.com/mtna/journal/v3/n3/full/mtna20146a.html
  4. “Androgen receptor down-regulation in prostate cancer with phosphorodiamidate morpholino antisense oligomers,” September 2004, https://www.ncbi.nlm.nih.gov/pubmed/15311058