In this post I am going to discuss some important and exciting areas of cancer research. Finally, progress is being made on the war against cancer with the advent of new technology. This is good news for all of us! Hopefully, in the very near future, they will finally discover ways to cure this often deadly disease.
This post is jam-packed with lots of information so you may need to read it slowly and more than once. Stay to the end for some valuable take home points.
Please note, in this post I will be using the terms endometrial cancer and uterine cancer interchangeably.
Cancer is a disease where cells have gone rogue. They are no longer playing nice with others and following a normal cell life cycle. Cancer cells are undergoing continuous cell divisions in an uncontrolled manner and even sending signals to change their environment!
Recent advances in research have led to the discovery of CANCER DRIVER GENES along with SIGNALING PATHWAYS.
Cancer driver genes and signaling pathways are intricately related. Mutations in the driver genes can activate or inhibit specific signaling pathways that promote tumor development and progression.
By discovering these different genes and pathways of cancer development, opportunities to develop new targeted treatments are being studied. There are also known natural remedies and supplements that can specifically target these genes and pathways.
Stay with me as I try to make it more understandable.
WHAT ARE CANCER DRIVER GENES?
Cancer driver genes are made up of two distinct gene types.
- ONCOGENES – These are genes that are normally inactivated and turned off in the cells. When “gain of function” mutations occur, mainly due to lifestyle and environmental factors, these genes become activated and expressed. This stimulates cancer cell growth and division.
- TUMOR SUPPRESSOR GENES – These genes are normally active and turned on in the cells. They become inactivated by “loss of function” mutations that block their functions. These genes normally inhibit cell proliferation, promote DNA repair and activate cell cycle checkpoints. When all this is turned off cancer cells can grow uncontrolled.
In this study they looked at 258 unique cancer driver genes. They found that the number of cancer driver genes varied among cancer types. Uterine and endometrial cancers had the highest number of cancer driver genes! Read More
In fact, studies show that endometrial cancer has the highest molecular complexity among common tumor types! Is it any wonder that standard of care therapies are not solving the problem and endometrial cancer mortality rates are on the rise?
COMMON CANCER DRIVER GENES IN ENDOMETRIAL CANCER
In an effort to keep things simple, I will use the abbreviations for these genes and signaling pathways as the full names are long and confusing!
- PTEN – this is a tumor suppressor gene and the most commonly mutated gene in endometrial cancer. Up to 77% of tumors have mutations in this gene
- PIK3CA – An oncogene that is very commonly mutated with 53% of tumors showing this abnormality
- PIK3R1 – an oncogene, 37% mutated
- CTNNB1 – an oncogene, 36% mutated
- ARID1A – a tumor suppressor gene, 35% mutated
- K-RAS – an oncogene, 24% mutated, often called the “undruggable” gene, its difficult to turn this one off
- TP53 – a tumor suppressor gene that codes for the protein p53; > 90% mutated in type II endometrial cancers and only 11% mutated in type 1
- POLE – mutations in this gene can cause an accumulation of DNA errors, leading to ultra-mutated tumors that may look aggressive. However, mutations of the POLE gene carry a very favorable prognosis and may not require chemotherapy or other treatments
- β-CATENIN – an oncogene, 20-25% mutated
WHAT IS A SIGNALING PATHWAY?
Signaling pathways are a series of chemical reactions that control cell functions such as cell division and cell death. These signaling pathways are multistage, complex circuits within cells.
A cell receives signals from its environment, like hormones or growth factors, which bind to specific receptors on the cell. This activates the first molecule in the signaling pathway, which then activates another molecule and so on until the cell function is carried out.
These signaling pathways and molecular networks are now being recognized for their critical roles in controlling important processes involved in the growth and survival of cancer cells. When these signaling pathways become disrupted, it leads to inhibition of apoptosis (programmed cell death), increased proliferation of cancer cells, invasion into nearby tissues and other processes of malignant tumors.
MOST COMMON SIGNALING PATHWAYS THAT ARE DYSREGULATED IN ENDOMETRIAL CANCER
- PI3K/Akt/mTOR pathway – this pathway is the most frequently altered in endometrial cancers and up to 80% have one or more alterations in this path. It often begins with loss of function of the PTEN gene and mutations in the PIK3CA gene. When this pathway is altered, it promotes proliferation, tumor growth and survival of cancer cells. It can also drive hormonal resistance.
- Wnt/β-Catenin pathway – this pathway is often abnormally activated in type-1 endometrial cancers by mutations in the β-catenin and/or CTNNB1 genes, which leads to tumor growth and invasion and metastasis, which can result in a poor prognosis. Signaling of this pathway is regulated by progesterone and estrogen hormones.
- MAPK/ERK pathway – this pathway is often activated via mutations in KRAS. This leads to increased proliferation signals to the cancer cells and more aggressive tumors.
- p53 signaling pathway – mutations in the TP53 oncogene are very common in the more aggressive types of endometrial cancer. This leads to loss of cell cycle control, increased tendency for DNA mutations and other genetic alterations to occur during cell cycle division and survival of damaged cells.
- Notch pathway – this pathway is involved in cell differentiation, proliferation and apoptosis. Abnormal activation of this pathway can lead to cancer cell proliferation. It can also facilitate epithelial to mesenchymal transition (EMT). EMT is a normal process in the body that aids in wound healing and tissue repair. In cancer this process causes tumor progression and the development of tumor cells with stem cell properties that play a major role in resistance to cancer treatments.
- Glutamine metabolism pathways – glutamine is the most abundant amino acid in the body. It is made by the muscles and transported through the blood to the organs. Cancer cells can use glutamine for survival and proliferation. It is now known that there is a connection between estrogen and glutamine metabolism in uterine cancer, making this another area for targeted treatments.
RECEPTOR TYROSINE KINASE (RTK) PATHWAYS
These are more signaling pathways that are also activated in cancer patients and are highly studied with targeted therapies.
- VEGFR1 and VEGFR2 – VEGF receptors, when stimulated by their protein, VEGF, stimulate the formation of new blood vessels, which is called angiogenesis. Tumors need these blood vessels to supply oxygen and nutrients as they grow. One thing that stimulates VEGF production is low oxygen concentration. When VEGF binds to these receptors it can also signal the PI3K/Akt and MAPK pathways. This promotes cell survival, migration and angiogenesis. High VEGF levels have been associated with lymph-vascular invasion, deep myometrial invasion, advanced tumor grades, metastasis to lymph nodes and worse clinical outcomes. Read More
- EGFR – is often overexpressed in cancer patients. The activation of EGFR enhances cellular responses to growth factors leading to increased proliferation and reduced apoptosis. It can also lead to the activation of several pathways including the PI3K/Akt and MAPK pathways. Overexpression of EGFR is often associated with more aggressive tumors and poor clinical outcomes.
- HER2/Neu – is a member of the EGFR family. Overexpression of this receptor can lead to aggressive tumor behavior. Here is a study looking at EGFR and HER2. 14-80% of serous cell cancers are HER2 positive. Read More
- Insulin Receptor pathway – this pathway regulates glucose metabolism and cellular growth. Insulin resistance is a big risk factor for endometrial cancer and increased insulin receptor signaling may contribute to tumorigenesis by promoting cell proliferation and survival.
- FGFR pathway – FGFRs are involved in numerous processes. FGFR2 mutations are found in about 10-16% of cases of endometrial cancer, especially type 1 EC. When this pathway is impaired, it can lead to increased cell survival and motility and tumor angiogenesis. FGFR alterations can contribute to growth and metastasis. Read More
Hopefully, you now have a basic understanding of some of the important cancer driver genes and signaling pathways as these are what they are targeting with the new therapies for endometrial cancer. Read More about signaling pathways here.
TARGETED THERAPIES
Research on these newer therapies is still in its infancy, but it is progressing rapidly.
In this brand new study, they have outlined new molecular classifications of endometrial cancer that are now guiding what treatments should be used. It is so important to ask your oncologist about all of these markers and what they mean for you before jumping into treatment!
The decision about adjuvant therapy selection has to be based not only on clinical data and histological type and stage of cancer, but, following international recommendations, has to include EC molecular subtyping. This review describes how molecular classification could support more optimal therapeutic management in endometrial cancer patients. Read More
Clearly, endometrial cancer is a very complex disease process, which is why we have to do all we can with standard of care treatments and natural remedies to get well and why combinations of drugs often work better than single drug treatments do.
GOALS FOR THE DIFFERENT TARGETED DRUG THERAPIES
- Stop angiogenesis – new blood vessel formation
- Inhibit oncogenes
- Restore function of tumor suppressor genes
- Use checkpoint inhibitors (immunotherapy) to allow the immune system to recognize cancer cells again and destroy them
- Stop signaling pathways that promote tumor growth and spread
- Reduce or block hormones in estrogen positive tumors
- Determine which genes and signaling pathways are associated with positive outcomes for certain treatment types
- Determine which genes or signaling pathways are associated with a poor prognosis and develop drugs to improve this
SOME OF THE NEWER TARGETED DRUGS BEING USED AND/OR STUDIED TO TREAT ENDOMETRIAL CANCER
Bevacizumab (Avastin) – angiogenesis inhibitor, attacks VEGF
Trastuzumab (Herceptin) – for HER2 positive cancers, especially serous cell carcinomas
Everolimus – mTOR inhibitor
Temsirolimus – mTOR inhibitor
Trametinib – MEK inhibitor for KRAS mutations Read More
Lenvatinib (Lenvima) – kinase inhibitor, VEGFR pathway
Rucaparib and Olaparib – PARP inhibitors (stop cancer cells from repairing DNA causing them to die)
DKN-01 – Experimental drug that targets a gene in the Wnt/β-Catenin pathway
Selinexor – investigational drug for the p53 pathway
Alpelisib – PIK3 inhibitor
Anastrozole – Aromatase inhibitor, blocks estrogen
Vistusertib – mTOR inhibitor
Letrozole – Aromatase inhibitor to block estrogen production
Multiple new immunotherapy drugs
Neoantigen peptide vaccines against endometrial cancer Read More
SCIENTIFIC REFERENCES HERE
For those who want to take a deeper dive into all this research
Molecular testing for endometrial cancer: An SGO clinical practice statement
Therapeutic Targets and Opportunities in Endometrial Cancer: Update on Endocrine Therapy and Nonimmunotherapy Targeted Options
Landscape of Endometrial Cancer: Molecular Mechanisms, Biomarkers, and Target Therapy
Endometrial cancer: a genetic point of view
Advances in Chemotherapy and Targeted Therapies in Endometrial Cancer
PARP Inhibitors in Endometrial Cancer: Current Status and Perspectives
TAKE HOME POINTS
I know this was a lot of very scientific, technical information and may be hard to understand. The reason for sharing this though is so you may begin to get a basic understanding of some of the advanced testing and different treatments that are out there. It will also be important later on as I discuss supplements and naturopathic treatments to target these genes and pathways as well.
It’s so important for precision based, personalized medicine to understand your particular cancer genetic profile. It can help guide treatments that work for you. Please see my other post on this topic here.
- Ask your oncologist to get testing done on your tumor tissue (from surgery or biopsies) to get the genetic profile of your particular cancer.
- Ask your oncologist specifically for the POLE mutation testing. If you have POLE mutations you may not need adjuvant treatments such as chemo and radiation and this can carry a very good prognosis!
- Get your VEGF level tested. This is a blood test your primary doctor can do. High levels can mean increased angiogenesis, metastasis and worse clinical outcomes. There are cancer drugs, but more importantly, natural supplements you can take to bring this down as well as hyperbaric oxygen therapy. VEGF inhibitors have lots of toxic side effects so you don’t want to take them if you don’t need them.
- Ask to have the HER2 status tested on the tumor tissues to help direct treatments. It is typically either positive or negative.
- Ask your oncologist about the targeted treatments that may or may not be effective against your particular cancer based on these tests.
- Although I am not a fan of clinical trials, for women with advanced, recurrent cancer that has become resistant to standard treatments, clinical trials with these newer targeted drugs may provide help. Make sure to ask your oncologist about this if you are in this situation. Read More
ONE THING YOU CAN DO TODAY ON YOUR HEALING JOURNEY
Today I want to encourage you to read this book. How to Starve Cancer Without Starving Yourself by Jane McLelland. This book is an excellent introduction to a lot of what I’m talking about in this post.
Jane McLelland was diagnosed with cervical cancer at age 30. She was failing traditional treatments for this aggressive cancer and it kept coming back when she took matters into her own hands and through research and trial and error saved her own life.
What she found she shares in this book about how to starve cancer using off-label drugs to block these various pathways for cancer growth. She presents it in easy to understand terms and you don’t have to be a scientist to get it.
I found this book very helpful in my own journey and have used a lot of the drugs she recommends to keep cancer at bay. I will be writing another post about this so stay tuned!
For I will restore health unto thee, and I will heal the of thy wounds, saith the Lord – Jeremiah 30:17