How scientists “cured” melanoma

When talking about Personalized Medicine, one of the recent shining examples of this concept in practice is in the treatment of melanoma. Melanoma is a cancer of the pigment cells called melanocytes and is most commonly diagnosed as a skin cancer. The prognosis for melanoma is dismal when caught at later stages where the cancer cells have spread into lower layer of the skin or throughout the body (see the stats in the image below). Treatment typically involves surgery to remove the cancer cells, followed by chemotherapy and/or radiation therapy, but the response to these treatments is low.

melanoma

There are two interesting personalized medicine examples for melanoma.  The first is in determining whether a low stage (I or II) melanoma has a likelihood of spreading.  Once a low stage melanoma has been removed by surgery, there is still a 14% chance that these patients will develop metastatic (melanoma that spreads) disease. To determine which patients are more at risk, a biotech company developed DecisionDx-Melanoma. This test looks at the expression of 31 genes and separates the patients into two groups based on the gene expression profiles.  One group only has a 3% risk of developing invasive melanoma within 5 years whereas the other group has a 69% chance.

However, whether the cancer progresses or not, treatment is still an issue. That is, it was until a few years ago when scientists found that  50-60% of all melanoma patients have a mutation in the gene called “BRAF.” This mutation tells the cancer cells to grow faster, so you can imagine that if you stop this signal telling the cancer cells to GROW, then they might stop growing and die. This is exactly what the drug PLX4032 (vemurafenib) does – it inhibits this mutated BRAF and stops the cancer cells from growing in 81% of the patients with this mutation (see the photo at the bottom of the post to see how dramatic this effect is).  On the other hand, in patients without this mutation, the drug has severe adverse effects and shouldn’t be used.  Because of this, doctors don’t want to prescribe this treatment to patients without the mutation.  Therefore, scientists created a companion diagnostic.  These are tests that are used to identify specific mutations before treatment to help decide what treatment to give (see image below). In the case of melanoma, this companion diagnostic tests if the patient has the BRAF mutation, and the patient is only treated with vemurafenib if they have this mutation.

This treatment was revolutionary with an incredible ability to cure melanoma. It was like melanoma was previously being treated with the destruction of a nuclear bomb, and now it is being treated with the precision of a sniper rifle – targeting the exact source of the cancer. So why is the word “cure” so obviously in quotes? Unfortunately, after continued therapy, the cancer relapses (see the image below). Imagine treating cancer cells being like closing a road- it’ll block up traffic (kill the cancer cells), but then you’ll be able to find back roads that get you to the same place.  In the case of cancer, the drug is targeting mutations in BRAF, and BRAF finds ways to evade the drug by mutating again (effectively removing the roadblock).  Or the cancer cells themselves may have other routes besides mutated BRAF making the cancer grow. So although this drug is a life extender, scientists have been working to combine it with other targeted drugs (blocking off alternative routes) to make it a long-term life saver.

melanoma_relapse

From the Journal of Clinical Oncology

What is Personalized Medicine?

bullseyeA few years ago I was asked to teach a course to adults at the ASU Osher School of Lifelong Learning about the Emerging Era of Personalized Medicine. This was exciting because it would give me the opportunity to help empower these adults to better understand their health, the science behind what make them sick, and what scientists and doctors are doing to cure them.  This was also a challenging course to develop because only a few years ago personalized medicine wasn’t the common buzzword like it is today. In fact, in early 2014, the Personalized Medicine Coalition contracted a research survey that found that 6 in 10 of people surveyed hadn’t heard of the term “personalized medicine” (see all results of the survey here). Despite the public being unaware of this huge advance, in the past few years, scientists and doctors continue to evolve this concept and medicine isn’t just “personalized” but now it can also be described as “precision,” predictive,” “individualized,” “stratified,” “evidence-based,” “genomic” and much, much more.

So what is new about this type of medicine?  Of course since the days of Hippocrates, doctors have provided care to patients that take their “personalized” needs in mind. Based on the patient’s symptoms and their experiences, the doctor provides treatment. But what if two patients have the same symptoms but different underlying diseases?  A fever and a headache could be the flu or malaria. Or two people could have the same disease, like breast cancer, but the underlying genetic changes are different so that the cancer should be treated differently for each patient.

The current concept of personalized/precision medicine uses each person’s individual traits (genetic, proteomic, metabolomic, all the -omics) and harnesses our molecular understanding of disease for the prevention, diagnosis, and treatment of disease.

personalized-med2The ultimate goal of personalized medicine is to improve patient health and disease outcomes. The graph above shows how better understanding the genetic and molecular causes of disease can improve health at all phases of disease progression.

  1. Knowing the risk factors that cause of disease (either environmental, like smoking, or genetic, like the BRCA gene mutation) can help to prevent disease before it starts by eliminating the risk factors or providing additional screening to catch the disease early.
  2. Biomarkers that detect disease before major symptoms can be used to treat the disease early, which usually has a better outcome than treating a disease that has progressed further (think stage 1 versus stage 4 metastatic cancer).
  3. Once a disease has been diagnosed, the molecular understanding of the disease can help determine what treatment the patient should receive (see below for an example).
  4. Biomarkers can also be used to predict whether the disease will progress slowly or quickly or whether or not a selected treatment is working.

For all aspects of personalized medicine, there lies the promise to make an enormous impact both on public health but also on decreasing the cost of healthcare.

breast_cancerLet’s use breast cancer as an example of how personalized medicine plays out in real life, right now. For breast cancer detection, breast self-exams and mammograms are typically used.  With personalized medicine, we now have an understanding of one of the genetic risk factors of breast cancer – mutations in the BRCA genes.  Patients at higher risk for developing breast cancer because of these mutations can be monitored more closely or preventative action can be taken. In the past, breast cancer treatment focused on treated with non-specific chemotherapy and surgery. Although both of these treatments are still of value, now doctors also test for the presence of certain breast cancer genes like Her2.  If Her2 is present in breast cancer cell, the drug Herceptin that specifically targets this Her2 gene can be used to specifically kill those cancer cells. If Her2 isn’t present, this drug isn’t effective, causes negative side effects and wastes time and money when a more effective treatment could be used.  Once breast cancer is diagnosed, a patient would be interested in knowing how quickly their cancer will progress. This used to be primarily based on the stage of the cancer, where stage 4 cancers have spread to other locations in the body so the prognosis isn’t great. Based on molecular markers, scientists have now created panels of biomarkers (Oncotype DX and MammaPrint) that predict breast cancer recurrence after treatment.

These personalized medicine-based tests and drugs are incredible. However, this is a field that both holds considerable promise and requires lots of work to be done.  For every incredible targeted therapy developed, there are patients that are still waiting for the treatment for their disease or the genetic variant of their disease.  In future posts, I’ll talk a lot about both the promise and the pitfalls of personalized medicine.

If you want to learn more about personalized medicine, check out this YouTube video with a cartoon comparing treatment with and without the concept of personalized medicine.

What is a biomarker? A cornerstone of personalized medicine.

What is a biomarker? Biomarkers are biological measures of health or disease and are a cornerstone for personalized medicine.Historically, diagnosing a disease was based on symptoms. This reminds me of a joke.  A patient goes to see the doctor and tells him “Doctor, I hurt everywhere.” The patients touches his head “I hurt here”, he touches his arm “I hurt here”, he touches his stomach “I hurt here” and on and on.  The doctor looks at him and says “I know what’s wrong with you!  You have a broken finger!”

No one wants to be diagnosed or misdiagnosed with a broken finger. This isn’t to say understanding symptoms and using this information to contribute to a diagnosis isn’t important.  But what if…
…symptoms don’t lead to an obvious diagnosis?
…two patients have the same symptoms, but different diseases?
…two patients have the same disease, but different causes – either the root cause is different or they both have lung cancer but the genetic mutations in each cancer is different.  In this case different treatments would be are needed.
…two patients have different diseases, but similar causes – maybe they both have the same genetic mutation in two different kinds of cancer –  so the same treatment can be used?

biomarkerThis is where biomarkers come in.  Biomarkers are things in the body that can be measured to give us information about a disease or other condition.  Biomarkers can be a variety of things including

  • Imaging methods
  • Genes (presence or absence)
  • Specific gene mutations
  • Proteins or antibodies
  • Metabolites
  • Microbes?

And these things can be measured to in some way indicate if the person is healthy or has a disease.  Other biomarkers may be used to detect a disease earlier than when the patient is showing symptoms.  Detecting a disease early may allow the patient to change a behavior to decrease the likelihood of developing the disease or to start treating a patient earlier when it is easier to successfully treat a disease. Biomarkers may also be used to determine the severity of a disease or whether or not the disease is progressing.

biomarker_types
Some biomarkers that you may be familiar with are cholesterol, temperature, and blood pressure.  There are a number of biomarkers for pregnancy. Home pregnancy tests look for the presence of the protein beta human chorionic gonadotropin (also called beta-HCG) in the urine.  This protein biomarker is in the blood after the zygote implants 6-12 days after fertilization.  Other biomarkers such as serum creatinine and liver enzymes are markers for kidney and liver function, respectively.

So what makes a good biomarker?  First, it needs to be different if the patients has a disease.  For example, higher than normal blood glucose levels may indicate that a patient has diabetes and these levels of blood glucose would not be found in a patient who didn’t have diabetes.  Second, the biomarker would have to correlate with the outcome.  What this means is that as the patient’s condition changes, the biomarker would also change. In the case of the patient with high blood glucose and diabetes, when the patient starts regulating their diet or taking insulin, the blood glucose levels will go down.  Third, biomarkers should be easy to access, and one of the main reasons for this is so that testing for the biomarkers isn’t too expensive.  Blood is a common location for biomarkers, including in our example of blood glucose levels.  Finally, biomarkers should be consistent.  It wouldn’t be useful to have a biomarker that changes based on whether it’s noon or midnight.  It needs to be dependent on the health of the patient.

Biomarkers are a cornerstone of personalized medicine because they allow clinicians to use symptoms along with measurable and quantifiable factors in the body (the biomarkers) to diagnose, track, and treat disease. Learn more about biomarkers in this YouTube video

What is a biobank? And why do scientists collect human tissue for research?

To understand what a biobank is and why they exist, it helps first to understand what type of “currency” is stored in the “bank” and what this “currency” will be used to purchase. Biobanks are a collection of “biospecimens” (the “currency”) and knowledge through research or preservation is often what can be “purchased” with this currency.  And as a quick FYI, biobank and biorepository are words that can be used interchangeably to describe the same thing.

Biospecimens can be any type of biological sample or material.  Seed biobanks, like the Svalbard Global Seed Bank in Norway, hold tens of thousands of seeds from over 4000 essential food crops.  The purpose of this biobank is to function as a back-up for seeds being stored in various countries. If a crop is wiped out because of disease or a zombie apocalypse, these seeds can be used to grow these crops again a biobank.

butterflies

photo credit Christian Guthier

The collection of birds, insects, butterflies, spiders and other animals and plants stored at the National Museum of Natural History at the Smithsonian Institute are also considered a biorepository.  There are a few reasons that these types of collections exist.  First, they are interesting to the public to show off the diversity of animals and plants found around the world and throughout time (I mean, who doesn’t like dinosaurs?).  But more than that, they are also immensely useful to scientists interesting in studying the animals themselves – including extinct animals, diversity, and evolution.

Biobanks that contain human tissue are most applicable to the study of humans and disease.  The biospecimens stored in these biobanks may include urine, blood, tissue (for example, extra tumor tissue removed during a surgery), feces (aka poop), cells (for example, cells scraped from the inside of the cheek or skin cells), cerebral spinal fluid, DNA or RNA.   The purpose of repositories that store tissue and fluids from people is to better understand diseases and use this understanding to develop molecular diagnostics and treatments. How is this done? Generally, scientists will compare biospecimens from many patients with a particular disease (for example, tumor tissue removed during surgery from patients with breast cancer or blood from patients with diabetes) to samples from patients who do not have that disease using one of those “-omic” analyses. Through understanding what causes the disease, methods can be devised to better detect the disease early or treatments can be developed to target the cause.

biobank_purpose

But you may be wondering how tissue biorepositories exist at all?  It is all because patients have been gracious enough to contribute some tissue, blood, skin, or nails for researchers to use in their research.  Biorepositories do not own this tissue and neither do the researchers – we are merely custodians of the tissue with the ultimate purpose to use the biospecimens for research.  The patient always comes first. Therefore, the first thing that is done before collecting tissue for research is to talk to the patient and explain why it is biobankers would like to collect and store their tissue.  The risks are explained and we ask for their permission through a process called informed consent (more on this in future posts).  If a patient does not consent to donate tissue for research, this does not affect their care in any way whatsoever.  It is the patients choice.  However, if they do agree to donate tissue, it will either be collected in the operating room (in the case of tumor tissue) or in pathology.  This tissue collection never disrupts medical care or diagnosis.  If all of the tissue is needed for diagnosing the patient, then that’s what happens and none is collected for research. Again, the patient and their medical care always come first.  If we are able to collect samples, they are stored in liquid nitrogen tanks until they are requested by a researcher.  We then make sure that the samples safely get to the researcher.biobank_workflow

Thousands (likely hundreds of thousands) of studies have relied on biospecimens to better understand the underlying disease in or to develop treatments.  For example, tissue from melanoma patients was used to identify a mutation found ~50% of patients who have melanoma.  This mutation can be specifically targeted by a drug that significantly improved progression-free survival in patients who typically have a dismal prognosis.  Even more studies on ongoing, with the goal of using knowledge gained from these priceless biospecimens to reach the promise of personalized medicine.