New Genomics-Based Personalized Colorectal Cancer Treatments
June 4, 2019
The term “colorectal cancer” is used to describe cancers that originate in either the colon or the rectum. These cancer types can also be referred to as either colon cancer or rectal cancer, respectively.
Colorectal cancer (CRC) is one of the most common and deadly types of cancer in the United States. It is the third most diagnosed cancer in both women and men in the US as well as the cancer type that leads to the third most cancer-related deaths in both women and men the US.
The existing treatments for colorectal cancers are generally pretty invasive, often requiring surgery and sometimes also chemotherapy or radiation, and even though new treatments are emerging, the overall survival rate of patients with CRC is low.
Colorectal cancer tumors that contain oncogenic RAS mutations are particularly difficult because they are more metastatic and aggressive and are more likely to be resistant to the standard therapeutic options.
More research is clearly needed to improve both the diagnosis of colorectal cancers so it can be detected at the earliest stages possible, when there are more treatment options available, as well as to improve the therapeutic options to really be able to treat every individual patient’s CRC in the manner that is most likely to lead to the best long-term outcomes.
What Causes Colorectal Cancer?
Colorectal cancers are an interesting class of human cancers because most of the time physicians aren’t able to identify the exact causes, but there are usually genetic (DNA mutations) and epigenetic (changes to DNA methylation and histone modification) components. The genetic causes of CRC are usually not heritable, but there are several risk factors, including some behavioral factors, that are associated with increased frequencies of developing CRC.
Some of the main colorectal cancer risk factors are:
- Certain family histories, such as other family members being diagnosed with CRC and being of African descent.
- General unhealthy lifestyle, such as smoking, heavy alcohol use, and lack of exercise.
- Personal history developing colon polyps or other cancer types.
- Older age, obesity, diabetes, and having chronic inflammatory diseases are all associated with increased risk of developing colorectal cancer.
How is Colorectal Cancer Diagnosed?
The most conclusive way to diagnose colorectal cancer is colonoscopy imaging for screening with a biopsy for analysis of any areas that look cancerous or suspicious.
Doctors recommend routine colonoscopies for individuals with average risk starting at the age of 50, and possibly earlier for patients with increased risks.
Most people consider colonoscopies invasive, or at least uncomfortable, so there are starting to be more non-invasive screening methods such as blood tests that measure genetic or epigenetic biomarkers. There is also a stool sample-based test called Cologuard that looks promising.
While the non-invasive diagnostic options for CRC offer certain comfort benefits, it is important to point out that biopsies that are part of colonoscopies are currently the best and only way for a conclusive colorectal cancer diagnosis.
What Treatments are Available for Colorectal Cancer?
As mentioned previously, the most common treatment for colorectal cancer is surgery, especially for early-stage CRC. The surgical treatments are also often combined with other therapeutic approaches such as radiation or drug treatments to improve results.
Treating Colorectal Cancer with Surgery
Surgeries to treat CRC can be relatively minor, such as removing polyps during a colonoscopy, or major, such as complete colon removal. The extent of surgery required is often determined by the cancer stage – more advanced CRC often requires more drastic surgery.
Surgical procedures are all risky and generally have side effects, but these risks and potential unwanted consequences are often worth accepting because CRC left untreated is so deadly.
Treating Colorectal Cancer with Radiation or Chemotherapy
Radiation therapy is not usually used to treat CRC, but it is sometimes used to shrink a tumor before surgery or used after surgery to ensure all of the cancer tissue was removed.
Chemotherapy treatment, in combination with surgery, is one of the more common ways to treat CRC. The most commonly-used chemotherapy for colorectal cancer is 5-fluorouracil (5-FU) given intravenously, sometimes given together with other drugs to improve its efficacy.
Most types of chemotherapy generally have significant side-effects due to their relatively non-specific cell killing activity (fast dividing healthy cells are killed, in addition to the cancer cells that are being targeted), highlighting the need for more targeted and personalized therapeutic approaches.
Treating Colorectal Cancer with Targeted Therapies and Immunotherapies
Drugs that specifically target only certain cancer cells are becoming more common. In particular, drugs that target a protein called vascular endothelial growth factor (VEGF) are effective for treating certain tumors because VEGF is a protein that these tumors rely on to develop the new blood vessels (a process called angiogenesis) needed to support their rapid growth.
Another protein being developed for targeted therapies is the epidermal growth factor receptor (EGFR). Some CRC tumors require EGFR for their growth, so when it’s inhibited by drug treatment the tumors can stop growing or even shrink.
These targeted therapies generally don’t work with CRC tumors with oncogenic RAS mutants, such as cancer cells with mutations in the KRAS gene. Because the especially aggressive and metastatic oncogenic RAS tumors do not respond to these specific treatments, it is becoming common to perform genetic screening to look for the RAS mutations in the tumor prior to starting the therapies.
Immunotherapies are one of the newer and more promising classes of anti-cancer drugs that have emerged in the past few years. One of the main ways that these therapies work is that they basically remove immune cell inhibitory checkpoints, allowing a cancer patient’s own immune response to more strongly fight off the cancer cells in their body.
These immunotherapies are often used as a backup plan if the standard of care treatment is not effective because there are significant risks involved when allowing the immune system to be more active than it usually would be. However, because immunotherapies are so effective in many cases, they are also being developed as first-line treatment options and this class of drugs is continuing to improve and will likely improve the cancer response outcomes for many patients in the future.
What’s Next for Personalized Treatment of Colorectal Cancer?
There are many therapeutic options available for treating patients with CRC, but the current options are not perfect and there is still a huge need for even better drugs and drug combinations that are more efficacious at treating CRC tumors.
A recent research study by a group of scientists and physicians in New York describing their new approach to using genomic data to provide personalized treatment for a KRAS mutant colorectal cancer patient was recently published in the journal Science Advances.
The researchers performed a genomic analysis of the mutations associated with CRC tumor cells in a patient with metastasized colorectal cancer that was resistant to standard care therapies. They found 9 mutations that appeared to be drivers for the majority of the tumors, including the oncogenic KRAS mutation and several other mutations that were previously known to be associated with CRC.
How Can Fruit Flies Help Cure Cancer?
Once the scientists identified the mutations that appeared to be responsible for the patient’s CRC, they generated Drosophila models that contained similar mutations. Previous studies by this group showed that their Drosophila model for CRC reproduced many aspects of human disease. Using the personalized fruit fly model for CRC with Drosophila versions of patient-specific mutations was a big advancement put forth by this study.
Having the personalized fruit fly allowed the researchers to quickly screen many different types of drugs and drug combinations to try to find the treatment options that would work best for this particular patient. The scientists tested 121 different FDA-approved drugs that have already been approved to treat tumors or had targets that were relevant to cancer.
This method identified a new drug treatment combination that hadn’t previously been investigated to treat CRC, trametinib (an FDA-approved drug to treat melanoma) plus zoledronate (an FDA-approved drug to treat bone disorders such as osteoporosis), as a potential therapeutic strategy for this patient.
At the time of the publication, the patient had been treated with the combination therapy consisting of trametinib and zoledronate for 11 months and he had a 45% reduction in his CRC tumors.
Is the Era of Personalized Medicine to Treat Cancer Finally Here?
This study represents a step forward and demonstrates the way we might be able to treat cancer in the future. “Cancer” is not a single disease, and even different kinds of cancer like colorectal cancer are not all the same. It is probably more accurate to think of cancer as a very broad category of disease in which cells divide out of control, and each different type of cancer and each patient might be unique and require a specific and unique treatment approach to achieve the best chance of winning the fight against each individual disease.
The researchers presented a new platform in their publication that allows the genomic profile of a cancer patient’s tumor to be analyzed and the mutations associated with that specific tumor to be recapitulated in a laboratory model organism such as the fruit fly to screen for the best drug combination to use to treat that cancer.
The scientists saw promising results in this study, suggesting that more people would likely benefit if this approach was expanded to include more patients and more types of cancers.
More research aimed to advance and innovate cancer treatments will hopefully continue to progress rapidly to give physicians more ways to treat the many millions of people that develop colorectal cancer and other cancer types.
Reference:Bangi, E. et al. A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer. Sci. Adv. 5: eaav6528. (2019)
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