Therapies Under Investigation
Therapies being developed for triple-negative breast cancer
Triple-negative breast cancer is when the cancer cells contain neither the ER- and PR-hormone receptors nor the HER2 receptor. There are fewer treatment options for this type of cancer, since it does not respond to hormone therapy or to HER2-targeted therapy. Surgery, radiotherapy and chemotherapy are the treatment options currently used for triple-negative breast cancer.
Many studies are underway to find more effective treatments for triple-negative breast cancer. Here is a brief overview of current research.
PARP is an enzyme involved in DNA repair. These inhibitors could be used for cancers with BRCA1 and BRCA2 gene mutations. In combination with BRCA inactivity, PARP inhibition prevents the DNA repair system from functioning and causes cell death due to excessive genetic instability. Several molecules are currently being studied (Olaparib, Talazoparib, Veliparib, Nivaparib, Rucaparib).
Bevacizumab works as an antibody to the vascular endothelial growth factor (VEGF), which promotes blood vessel growth. VEGF is overexpressed in several types of triple-negative cancer. Decreasing neovascularization can decrease tumour growth. Bevacizumab is currently used to treat other cancers, such as colorectal and lung cancer.
EGFR is sometimes overexpressed in triple-negative breast cancer. An EGFR inhibitor being studied is Cetuximab. Results have been disappointing, but researchers believe this inhibitor may be effective for a specific subtype of triple-negative breast cancer. Other studies are ongoing.
SRC enzymes are often overactivated in triple-negative cancer. One of the molecules currently under investigation is Dasatinib. The preliminary results are disappointing, despite promising preclinical studies. Researchers are evaluating the effectiveness of SRC inhibitors when given in combination with other treatment options, such as EGFR inhibitors.
Glembatumumab vedotin is a cytotoxic antibody that targets the glycoprotein NMB, a protein that plays a role in tumour invasion and metastasis development and is overexpressed in triple-negative breast cancer. The antibody is coupled with a cytotoxic drug.
Immunotherapy: A promising treatment under investigation
Immunotherapy is one extensively studied type of cancer treatment.
Immunotherapy targets the immune system. Several immunotherapy strategies use the immune system to destroy cancer cells. Some seek to stimulate immune cells and destructive mechanisms, while others try to block or suppress the mechanisms that protect cancer cells.
Benefits of immunotherapy
- Because it is more targeted than chemotherapy, immunotherapy causes fewer side effects and can be administered over a longer period of time.
- It can be given in combination with other therapies without increasing the treatment toxicity.
- There is less chance of developing resistance with immunotherapy because the immune system targets several antigens simultaneously. Immunotherapy works despite the adaptations of the cancer cells.
Trastuzumab is considered immunotherapy because it consists of an antibody, which is a component of the immune system. It is currently the only approved immunotherapy.
Here is an overview of the molecules currently under investigation:
A vaccine is an injection of a small inactivated protein. Immune cells learn to recognize this protein and are ready to trigger an immune response if they encounter it again. They will then be able to eliminate the cells that possess this protein.
Cancer vaccines are made from proteins specifically expressed by cancer cells. Cancer vaccines therefore train the immune system to recognize and eliminate cancer cells.
Immune-system checkpoints and immune-response modulators are a class of drugs that can block an inhibitory molecule or activate an immune-response stimulator molecule to generate an anticancer effect.
This therapy aims to transfer T lymphocytes, a class of immune cells that participate in the destruction of foreign bodies. This therapy proposes to take T lymphocytes from a patient, genetically modify them or chemically treat them in the laboratory to make them more efficient. The improved cells are then reinjected into the patient to improve the immune system’s anti-cancer response.
This therapy utilizes modified viruses able to attack cancer cells. They target only the diseased cells and lead the immune system to recognize and destroy infected cells.
Antibodies are produced in the laboratory and target antigens (proteins) produced specifically by cancer cells. Once the antigen is recognized by the antibody, the targeted protein is inactivated. Immune cells detect this interaction and eliminate the cancer cell carrying the antigen.
This is the mechanism used by Trastuzumab, a treatment used for HER2-expressing cancers. New antibodies are being developed to improve treatment efficacy and provide alternatives in case of Trastuzumab resistance.
Immune adjuvants are substances that strengthen the patient’s immune response. Adjuvant immunotherapies use ligands (the molecules that bind to a protein to activate it) to help control the immune response (activate or block the response).
The emergence of treatment resistance
A problem in breast cancer treatment is when the cancer cells become resistant to treatment and a drug is no longer effective.
Mutations appear because cancer cells proliferate profusely and their genetic material is unstable. These new mutations cause the cells to adapt and find new ways to grow, in spite of the treatment.
Here are some of the adaptations that allow cancer cells to develop resistance to breast cancer treatment:
- Overexpression of HER2, EGFR or IGFR1 (insulin-like growth-factor receptor)
- Overactivation of the PI3K/Akt/mTor and SRC signalling channel
- Loss of expression or mutation of the estrogen/progesterone receptor or one of its co-activators (a protein that regulates its activity)
- Mutation of a cell cycle regulator
- Presence of stem cells
- Loss of PTEN expression
- Expression of a HER2 fragment that does not have the Trastuzumab binding site
- Coupling between HER2 and IGFR1 (insulin-like growth-factor receptor)
- Overexpression of c-MET, a tyrosine-kinase receptor
When there is resistance to treatment, the disease progresses and a new type of treatment must be administered.
Because treatment resistance reduces the effectiveness of breast cancer therapy, many studies are underway to find good strategies to counter resistance. Here are some of the promising ones under investigation:
- Everolimus, an mTor inhibitor used in combination with hormone therapy or Trastuzumab
- CDK4 and CDK6 inhibitors used in combination with hormone therapy or Trastuzumab
- PI3K inhibitors
- HDAC inhibitors
- Combination of targeted and standard therapies
- IGFR1 inhibitors
- c-MET inhibitors
- SRC] inhibitors
- Use of biomarkers to determine the patient’s response and thus focus on the best option early on