Novel Approaches to the Diagnosis and Treatment of Cancers

Highlights

• Cancer treatment is moving from generalized approach to a personalized approach
• Newer drugs are being developed for cancers like gastrointestinal stromal tumors (GISTs) in patients with specific genetic abnormalities
• Liquid biopsies are used to detect treatment response and tumor gene resistance to treatment in a blood sample without the need for repeated tumor biopsies

Experts feel that treatment of cancer is moving from a generalized treatment for all patients with a particular type of cancer, to personalized treatment where each person will be treated by medications that they are most likely to respond to.

Personalized treatment has its roots in the understanding of the molecular composition of tumors and using drugs that will act at a particular target – a type of therapy called targeted therapy.

Two ongoing studies highlighting the effectiveness of treating patients with gastrointestinal stromal tumors (GISTs) with specific genetic abnormalities have been presented at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics at Munich, Germany.

GISTs are digestive tract tumors that may be benign or malignant and are usually located in the stomach and intestines. Localized tumors can be treated through surgery. Targeted therapy with imatinib mesylate and sunitinib are used in the treatment of GISTs that cannot be surgically treated. These medications target molecules only in cancer cells without affecting normal cells, thereby causing less side effects.

Genetic factors are often responsible for the development of GIST. GISTs usually occur due to mutations in the KIT and PDGFRα genes, which regulate the production of proteins from the family called tyrosine kinases. Abnormalities in these genes cause cells to proliferate, resulting in cancer. Drugs like imatinib mesylate and sunitinib target tyrosine kinase but may become infective after some time due to the development of resistance.

In a small clinical study, researchers found that a drug under development, currently called BLU-285, is effective in the treatment of GISTs with KIT or PDGFRα mutation. The new drug overcomes the mechanism that makes drugs like imatinib ineffective.

Advertisement

In the study, 36 patients with advanced GIST and with mutation in the KIT or PDGFRα who progressed despite two prior treatments with medications like imatinib were administered BLU-285 in a dose of 30 to 400mg a day. The researchers found that:

• The drug appears to have remarkable anti-tumor activity. However, the study is still in its initial stages and long-term effects are not yet known
• The drug appears to be relatively safe.
• Nine people discontinued taking part in the study since the cancer continued to progress in these patients.

Another drug in development, DCC-2618, acts similarly to BLU-285, but is effective in patients with a broader range of alterations in the cancer-causing genes, and shows promise in the treatment of GIST and difficult-to-treat brain cancers like glioblastoma multiforme. Researchers have begun testing the drug in a small number of patients in doses of 20mg to 150mg given orally twice a day for 28 days. Initial results of the study are positive.

Advertisement

The above studies used a technique called liquid biopsy in their studies. Cancers are diagnosed and followed up based on tissue biopsy. Doing a tissue biopsy repeatedly has the following disadvantages:

• Tissue biopsy is an invasive test and causes some discomfort to the patient
• The patient has to bear an additional cost for the procedure
• There is a possibility of injury to normal tissue during the procedure

Liquid biopsy, on the other hand, only needs a blood test. The drawn blood is analyzed for circulating tumor DNA which is shed by the tumor cells to detect genetic mutations.

Another study presented at the same conference evaluated the use of liquid biopsies in cancer. The patients’ blood was collected when they stopped responding to cancer treatment and the cancer started to progress. During the test, the DNA was analyzed to detect which mutations could have possibly led to the resistance to treat. The test could detect the following:

• Molecular changes responsible for resistance to treatment in nearly 80% of patients
• Multiple resistance mechanisms. The primary tumor and each of its metastases may have a different pattern of tumor resistance. It is not possible to detect these multiple resistance mechanisms through biopsy of a single tumor, but is possible through liquid biopsy. Liquid biopsies could detect additional alterations as compared to those detected by tumor biopsy.
• Novel mechanisms of resistance. This knowledge can be used to develop treatments to overcome resistance.

In the first study with BLU-25, liquid biopsy was able to show a response to treatment by demonstrating a lower level of circulating DNA within two weeks of treatment with BLU-25. In the second study involving DCC-2618, liquid biopsy detected multiple mutations in cancer cells that result in resistance to treatment. Liquid biopsies have the potential to change diagnostics of cancer in the future.

References

1. ENA2016 NEWS: ‘Revolution in our understanding of cancer’ - (http://www.ecco-org.eu/Global/News/ENA/ENA-2016-PR/2016/11/ENA2016-Revolution-in-our-understanding-of-cancer)
2. General Information About Gastrointestinal Stromal Tumors - (https://www.cancer.gov/types/soft-tissue-sarcoma/patient/gist-treatment-pdq)

Source-Medindia