A Deeper Dive into the Nature Research Scientific Report on TUSC2 and Triple-Negative Breast Cancer

Genprex recently announced that independent researchers found that company’s TUSC2 (tumor suppressor candidate 2) prevented tumor growth in triple-negative breast cancer (TNBC). These independent researchers have no affiliation with Genprex.

Genprex takes a deeper dive into the data of the study to provide analysis and a better understanding of what the study found and what it means for TUSC2.

The study, “MicroRNA-138 is a Prognostic Biomarker for Triple-Negative Breast Cancer and Promotes Tumorigenesis via TUSC2 repression,” takes a look at one particular subtype of breast cancer, triple-negative breast cancer (TNBC).

Triple Negative Breast Cancer

According to the National Breast Cancer Foundation, TNBC occurs in about 10-20 percent of diagnosed breast cancers, and is more likely to affect younger patients (under the age of 50 years old), African Americans, Hispanics and those with a BRCA1 gene mutation.1,5

A diagnosis for TNCB means that the patient does not have any of the three most common types of receptors that enable breast cancer growth, including estrogen, progesterone and the HER2 gene, thus the name for triple-negative breast cancer.TNBC progresses rapidly and is more likely to metastasize to the brain and viscera relative to HER2+ cancers.5

Treating TNBC with today’s emerging targeted therapies and immunotherapies are typically ineffective because these receptors are not present. This makes TNBC difficult to treat, and as an aggressive cancer, it is increasingly a feared diagnosis. With few treatment options, most TNBC patients must undergo a lumpectomy, a mastectomy, radiation, chemotherapy or a combination of these treatments.2TNBC patients are significantly less likely to survive than other breast cancer patients following the first metastatic event.5

The Role of MicroRNA-138

MicroRNA, or miRNA, help to downregulate gene expression in a variety of manners.3Thousands of miRNAs have been identified, and miRNAs possess the capacity to target between tens and hundreds of genes simultaneously. They perform a key role in tumorigenesis as important modulators in cellular pathways by regulating target gene expression through translation repression or mRNA degradation.4

Increased miR-138 expression is highly specific to TNBC, and the Nature report notes that miR-138 correlates with poor prognosis in patients, and it is functionally relevant to cancer progression.

The independent researchers explored the role of miR-138 in TNCB and found that it is a specific molecular signature of TNBC and a prognostic biomarker for breast cancer pathogenesis. Researchers also found miR-138 to be a pro-survival oncomiR for TNBC, meaning that overexpression of the gene leads to cancerous tumor growth.6Lastly, when miR-138 is depleted, it leads to apoptotic cell death in vitroand prevents tumorigenesis in vivo. In finding a way to deplete miR-138, this could lead to cancer cell death.

The Role of TUSC2

The independent researchers also found that TUSC2, which is the active agent in Genprex’s lead drug candidate, was a direct target downregulated by miR-138. TUSC2 expression is elevated and TUSC2 protein levels are enhanced following miR-138 knockdown.In TNBC mouse model studies using TUSC2, tumors were barely detectable under miR-138 knockdown conditions, and the implantation of TUSC2 overexpressing cells yielded tumors that are significantly smaller than those in the control group. TUSC2 expression was found to substantially mimic miR-138 knockdown and prevent tumor growth, revealing a potential new treatment for TNBC.

Genprex’s Oncoprex

Genprex is conducting clinical and pre-clinical research to evaluate the effectiveness of TUSC2 when combined with targeted therapies and immunotherapies for non-small cell lung cancer. However, existing pre-clinical data also suggest that TUSC2 may be effective against glioblastoma, head and neck cancer, kidney cancer, and soft tissue sarcomas. These studies, and more information on TUSC2, can be found on Genprex’s website.

Oncoprex™ immunogene therapy, Genprex’s lead drug candidate, has a multimodal mechanism of action whereby it interrupts cell signaling pathways that cause replication and proliferation of cancer cells, re-establishes pathways for programmed cell death, or apoptosis, in cancer cells and modulates the immune response against cancer cells. Oncoprex has also been shown to block mechanisms that create drug resistance.

Genprex uses a unique proprietary technology platform that delivers cancer fighting genes by encapsulating them into nanoscale hollow spheres called nanovesicles, which are then administered intravenously and taken up by tumor cells expressing proteins that are missing or found in low quantities. The company believes that this platform allows a variety of cancer fighting genes to be delivered to the patient to fight against several types of cancer.

The company currently holds a portfolio of more than 30 issued patents covering its technologies and targeted molecular therapies.

*Oncoprex is currently in development and is not FDA approved.

References:

  1. www.nationalbreastcancer.org. (2019). Triple Negative Breast Cancer :: The National Breast Cancer Foundation. [online] Available at: https://www.nationalbreastcancer.org/triple-negative-breast-cancer [Accessed 12 Sep. 2019].
  2. Cdc.gov. (2019). Triple-Negative Breast Cancer | CDC. [online] Available at: https://www.cdc.gov/cancer/breast/triple-negative.htm [Accessed 12 Sep. 2019].
  3. SigmaAldrich.com. (2019). miRNA (microRNA) Introduction. [online] Available at: https://www.sigmaaldrich.com/life-science/functional-genomics-and-rnai/mirna/learning-center/mirna-introduction.html [Accessed 12 Sep. 2019].
  4. Tan W, Liu B, Qu S, Liang G, Luo W, Gong C. MicroRNAs and cancer: Key paradigms in molecular therapy. Oncol Lett. 2018;15(3):2735–2742. doi:10.3892/ol.2017.7638
  5. Nama S, Muhuri M, Di Pascale F, Quah S, Aswad L, Fullwood M, Sampath P. MicroRNA-138 is a Prognostic Biomarker for Triple-Negative Breast Cancer and Promotes Tumorigenesis via TUSC2 repression. Nature Research. 2019; 9:12718. doi.org/10.1038/s41598-019-49155-4.
  6. Cancer.gov. (2019). NCI Dictionary of Cancer Terms Oncogene. [online] Available at https://www.cancer.gov/publications/dictionaries/cancer-terms/def/oncogene[Accessed 12 Sep. 2019].