Tackling Breast Cancer: Usage of Disarib for targeted treatment

 

One of the leading causes of death globally, (accounting for around 1 in 9 men, and 1 in 12 women), is Cancer. Cancer is a large group of diseases that can start in almost any organ/tissue of the body when cells grow uncontrollably, go beyond their usual boundaries to invade surrounding tissues, and/or spread to other organs. Among men, the most common types of cancer include lung, prostate, colorectal, stomach, and liver cancer. Among women, breast, colorectal, cervical, and thyroid cancer are commonly observed. In this article, we shall focus on Breast Cancer.

 Breast Cancer involves the abnormal growth of breast cells, leading to tumor formation in many cases. The Breast Cancer cells begin inside the milk ducts and the milk-producing lobules of the breast. We shall focus particularly on the Triple Negative Breast Cancer (TNBC), here. The Triple Negative Breast Cancer is a prime example of Invasive Breast Cancer. Invasive Cancer can spread to nearby lymph nodes or adjacent organs of the body (that is, they can metastasize).

Unlike most Breast Cancer cases, the TNBC cells lack the following:

1.    Receptors for Estrogen (ER)

2.    Receptors for Progesterone (PR)

3.    Epidermal Growth Factor Receptor 2 (HER2)

The absence of the above three receptors gives the cancer its name. TNBC is known for its difficulty in diagnosis and treatment.

 TNBC is most likely to affect:

1.    Women and AFAB individuals aged 40 or younger

2.    Individuals with BRCA mutations (that is, inherited genetic mutations that increase chances of Breast Cancer)

3.    Black or Hispanic Individuals

 A 2016 study revealed that TNBC spreads at a tremendously faster rate compared to other types of Breast Cancer. In comparison, HER2-positive breast cancer tumors grow 0.859% each day, while TNBC cancer tumors grow 1% each day.

 Some existing treatments for TNBC include:

1.    Chemotherapy

2.    Immunotherapy

3.    Surgery

4.    Targeted therapy

5.    Radiation therapy

 It has been observed that cancer cells show a high downregulation in apoptotic activity. Apoptosis is the body’s way of getting rid of unwanted/abnormal cells, through a series of molecular steps and reactions. Anti-apoptotic proteins, prevent apoptosis by inhibiting specific steps of the cell death process. Certain anti-apoptotic proteins, such as BCL-2 family members, are highly upregulated in cancer cells.

 BCL-2 is highly expressed in approximately 75% of primary breast cancer. Around 41% of TNBC and 19% of basal-like tumors show high BCL-2. Due to the key role BCL-2 plays in cancer cell development, it has been labeled an ideal target for cancer therapy. Targeted therapies are being developed with the main goal being inhibition of BCL-2 activity.

  A small molecule inhibitor, namely Disarib, has been developed as a selective BCL-2 inhibitor. Disarib induces cytotoxicity in TNBC cell lines without causing cell cycle arrest. It targets the mitochondrial membrane proteins, which results in the loss of mitochondrial membrane potential thus possibly activating intrinsic apoptotic pathway. It was also observed that the colony-forming ability of TNBC cell lines was significantly reduced upon Disarib treatment. The colony-forming property is a sign of undifferentiated cancer stem cells.

 

Fig 1. Disarib Molecule

The Human TNBC cell line-derived Xenograft models used for this study were: MDA-MB-231, MDA-MB-468, and MDA-MB-453. Upon treating the TNBC cell lines, it was noted that Disarib inhibited tumor growth.

 In TNBC, one of the reasons for metastasis is the EMT program activation (Epithelial-to-Mesenchymal Transition). This gives cancer cells the ability to migrate. EMT is a process where cells gain mesenchymal characteristics due to the loss of tight and adherent cell junctions. Treating the Xenograft models with Disarib downregulated the expression of these EMT Markers and transcription factors, thus inhibiting the migratory activity of TNBC cells.

 The energy required for the metastasis process in cancerous cells comes from glycolysis. Cancer cells shift from oxidative phosphorylation to glycolysis, under aerobic conditions. They do so to rapidly generate energy and meet the excess energy demand for metastasis. However, upon Disarib treatment of the TNBC Cell line, there was a significant reduction in glycolysis and a mild decrease in oxidative phosphorylation. Thus, hindering the tumor metastasis process.

 In conclusion, this study showed that Disarib serves as a promising approach for the targeted treatment of TNBC, by targeting BCL-2 and altering the ideal conditions required for cancer cell survival, metabolism, and migration. Beyond TNBC, this research can help in exploring BCL-2 targeted treatment in other cancers showcasing BCL-2 overexpression.

 

REFERENCES:

1. Manjunath M, Ravindran F, Sharma S, Siddiqua H, Raghavan SC, Choudhary B. Disarib, a Specific BCL2 Inhibitor, Induces Apoptosis in Triple-Negative Breast Cancer Cells and Impedes Tumour Progression in Xenografts by Altering Mitochondria-Associated Processes. International Journal of Molecular Sciences [Internet]. 2024 Jun 12 [cited 2024 Jul 5];25(12):6485. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11203414/

2. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: A Cancer Journal for Clinicians. 2023 Jan 12;73(1):17–48.

3. https://www.who.int/health-topics/cancer#tab=tab_1

4. https://my.clevelandclinic.org/health/diseases/21756-triple-negative-breast-cancer-tnbc

IMAGE SOURCE:

1. https://shareing-careing.org/what-is-triple-negative-breast-cancer/

2. https://www.chemsrc.com/en/cas/1998149-15-7_1561448.html