Beyond DNA — Studying RNA to Understand Treatment Resistance and Prescribe Truly Personalized Cancer Therapies

Cancer scientists are going beyond DNA to study RNA and the transcriptome. A recent Omicure et al. article in the Journal of Clinical Colorectal Cancer highlights how RNA sequencing is revealing further characteristics of cancer than those known via DNA. This can potentially lead to additional therapeutic options, particularly once treatment resistance has set in. 

Background: Cancer, Genomics, Precision Medicine, and DNA

Cancer is a complex set of diseases whose traditional treatments commonly result in harsh side effects and lasting collateral damage.

People whose cancer is metastatic — meaning that it has spread from its initial site such as the lung, breast, colon, etc., to elsewhere in the body — face unique treatment challenges due to what is known as resistance. After a certain point, treatments that have been working stop being effective and the cancer starts to grow again. Metastatic cancer, also known as advanced or stage IV, is lethal.

Progress in both cancer research and technology has been paving the way for personalized or targeted treatments to better serve patients. This is known as precision medicine, which in cancer specifically, relies on molecular diagnostics. According to the National Cancer Institute,

Molecular diagnostic tests detect specific biologic molecules, or biomarkers, in a patient’s tissue and fluid samples. Molecular diagnostic tests can be used to select a cancer therapy and/or to monitor the effects of a treatment based on characteristics of or changes in the biomarker.

Usually, these biomarkers are found when a tumor’s DNA is sequenced. Some well-known biomarkers include ROS1, ALK, and HER2/ERBB2, and targeted treatments which are directed at these molecules can be highly effective. However, even targeted therapies end up encountering resistance when up against stage IV cancer. Gaining a complete understanding of the causes of this resistance is key to refining and developing next generation cancer treatments.

From DNA to RNA: Towards Truly Personalized Cancer Medicine

With that in mind, scientists are beginning to dive deeper into the field of genomics, going beyond DNA to study RNA and the transcriptome. Indeed, the field of oncology has begun to study the possibilities for RNA sequencing to reveal further hallmarks of cancer than those known via DNA, and therefore potentially lead to additional treatment options, particularly once treatment resistance has set in.

Recently, OmiCure, Personalized Cancer Medicine, Ariana Pharma, and Private Health, Inc.  published a scientific article in the Journal of Clinical Colorectal Cancer reporting on the case of a 49-year old woman who was diagnosed and treated for stage IIIB colon cancer with chemotherapy in 2015-16.

When about a year later the patient’s cancer progressed to stage IV, she had surgery to remove the metastases and was stable for about a year. Then, new areas of spread were detected, molecular studies revealed she had HER2 amplification (i.e., high copy numbers of HER2), and she joined the MyPathway clinical trial to gain access to treatment targeting those biomarkers (a combination of trastuzumab-pertuzumab). This resulted in a partial remission which lasted approximately one year. As the patient’s cancer continued to progress, she and her medical team tried various other treatment strategies which, like the ones before, ended up meeting resistance. By January 2020, another biopsy revealed that her cancer was still HER2 amplified, with no new genomic abnormalities.

As it appeared that all known options to treat this patient’s cancer had been exhausted, her team decided to perform RNA sequencing. This allowed them to perform gene expression analysis on two of her previous biopsies and compare the results to healthy colon tissue.

In retrospect, the team found that had they sequenced the tumor’s RNA on a regular basis throughout the patient’s course of treatment, they would likely have discovered information that could not be found via solely studying the tumor’s DNA. And, this valuable information could have helped them decide what and when to prescribe, and what not to prescribe, given the effects on treatment resistance of certain biomarkers found uniquely via RNA sequencing. In other words, with RNA it is possible “to check if some of the results obtained from DNA analysis actually translate or not in changes in gene expression, to see if it makes sense to try to bring it down or up. And also to check the levels of other genes involved in treatment resistance, to see how to overcome those.”

Dr. Michael CASTRO MD Personalized Cancer Medicine, PLLC
Dr. Michael CASTRO MD Personalized Cancer Medicine, PLLC

"There is so much unanticipated and clinically relevant information in gene expression analysis, practicing without it will soon come to be seen as the medical equivalent of crossing the street looking in only one direction."

For the colon cancer patient in the case report, for example, the team found that it would have been possible to “avoid one of the prescribed lines of HER2-targeting treatment that had been prompted by misleading amplification DNA results.” This would have spared her unnecessary added side effects as well as financial toxicity. 

The team concluded that “in the chess game of disease control, such results may deliver unanticipated insights which re-direct therapeutic planning in crucial ways.”

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