Personalized cancer therapy steadily advances, as highlighted by key articles in Science and Nature this month. This blog tallies how individualized therapy is progressing against cancer, the world’s most challenging group of deadly diseases.
Following a look at the context of personalized cancer treatment, we’ll look at the application of this therapy to unique individuals and their cancers:
– Tumor Location.
– Targeted Therapies.
– Genetic Markers.
– Genomic Statistical Analysis.
– Modifying the Patient’s Immune Cells.
– Nanoscale Drug Testing.
– Fruit Fly Avatars.
– Better Models for Clinical Trials.
The Context of Personalized Cancer Therapy
In the U.S. and other developed countries, heart disease and cancer dominate the causes of death, as shown in this table from page 18 of Health, United States, 2016, published by the Centers for Disease Control.
Each of these “big two” causes of death outnumbers lesser causes by many times.
Yet cancer is not one disease, but a large number of diseases. Their common characteristic is abnormal tissue growth with the potential to spread to other parts of the body.
Our understanding of cancer has changed many times throughout history. Two thousand years ago, cancer treatment called for surgery or for purgatives.
Modern treatments recognize cancer’s propensity to spread to other organs. For that reason, cancer therapies may include both of the following:
– Local treatments such as surgery, radiation and hyperthermia therapies.
– Systemic treatments such as chemotherapy, both hormonal and targeted.
Chemotherapy employs chemical agents that kill cancer cells; however, they can weaken or kill non-diseased cells in the body. For this reason, the oncologist must carefully manage chemotherapy. Chosen chemicals must be effective against the patient’s type of cancer, but dosage must minimize side effects to vulnerable cells. Those include bone marrow, the digestive tract and hair follicles.
Recent cancer therapies rely on microbiological and genomic analysis of the patient’s particular cancer.
We can view the modern history of cancer as an evolution of personalized cancer therapy. Let’s step through recent developments using personalization as our roadmap.
Tumor Location as Personalization
Although all cancers appear as unwanted tissue growth, their progression depends on the organ they infect. In the 1940s various chemicals were first tested for cancer suppression. It turned out that chemotherapy was most effective when using several chemicals together. This combined attack made it more difficult for the cancer to mutate to avoid destruction.
This approach led to a family of treatments, each one optimized for cancer occurring in a specific part of the body. Thus the first personalization of cancer therapy was simply to choose a treatment based on the organ of the cancer’s origin.
Personalization through Targeted Therapies
In the late 1990s oncologists chose chemical agents to target specific functions of cancer cells. These functions included stopping the ability of the cells to divide and spread, and blocking them from forming the new blood vessels they need to grow.
However, targeted therapies required more than blind application. Doctors found it necessary to test a person’s cancer to see which treatment agents would be most effective. In some cases, they also had to conduct genetic tests to determine whether a particular treatment posed too much risk to that individual.
Thus personalized cancer treatment continued to evolve with targeted therapies added to the oncologist’s toolkit.
Personalization through Genetic Markers
As noted above, cancer treatments have mostly been based on the originating organ. However, genetic testing provided a different perspective.
The gene mutations in certain cancers produce surface protein fragments visible to T cells, which guide the body’s immune response. Merck initially developed the drug Keytruda (Pembrolizumab) to target these fragments in melanoma (malignant skin cancer).
Some 4% of all cancers show the surface proteins that Keytruda addresses. For this reason, researchers at Johns Hopkins ran a clinical trial using Keytruda against a variety of other cancers: colorectal, breast, prostate and pancreatic. The tumors of most of these patients shrank or even disappeared. The Food and Drug Administration was so startled by this broad success that they approved the further use of Keytruda on all types of cancer matching the appropriate genetic markers. Their approval even applies to types of solid tumor against which the drug has never been tested.
Journalists describe this remarkable approval, the first of its kind, as authorizing “tissue-agnostic” drugs1. A gold rush is underway as pharma companies hurry to get additional genetically targeted drugs approved. Seven additional drugs, from four additional drug makers, are presently working their way through the testing and approval process.
Meanwhile, an even more personalized T-cell approach is showing good success in treating some cancers. Trials in Boston, Massachusetts with 6 patients and in Mainz, Germany with 13 patients have been very successful against melanoma, including melanoma that metastasized.
Personalization through Genomic Statistical Analysis
The above success suggests that cancer’s genetic markers could be a breakthrough that would conquer cancer. However, thus far only 10% of cancer patients who undergo molecular testing show gene aberrations that suggest a known or possible treatment.
Each cancer contains many mutated genes. However, in most cases doctors don’t know which ones are critical to the cancer, and do not have drugs available that target those mutations.
An approach being taken at Dana-Farber Cancer Institute is to compare the DNA sequence from a patient’s cancer with normal DNA from the same patient. They use statistical analysis to determine which of the differences are most likely to be unique to the cancer and occur more often than you would expect from random mutation. Researchers hope to home in on those genetic aberrations that can serve as targets for attacking the cancer. That may lead to more cancers being treatable based on their genetic markers.
Personalization through Modifying the Patient’s Immune Cells
CAR-T2 (chimeric antigen receptor T-cell therapy) offers a different approach to personalized cancer treatment, one that has become important during the last few years. It involves removing immune cells from a cancer patient, genetically modifying them to fight the patient’s particular cancer, then transfusing them back into the patient. CAR-T has been a particularly powerful tool against leukemia and lymphoma.
These cells are difficult to produce since the oncologist must design each portion for a specific individual. Production involves genetic engineering and the risk of working with live cells. A batch requires weeks of work by highly trained technicians and costs tens of thousands of dollars.
Since each research group can only treat a few patients at a time, demand greatly exceeds the supply of this type of therapy. Companies are jumping on it, expecting a booming market in this treatment as they discover ways to streamline the work to serve more patients.
Personalization through Nanoscale Drug Testing
In another approach, Technion University is using nanotechnology to test a variety of cancer drugs against an individual patient’s tumor. They use synthetic DNA sequences as “barcodes” that allow them to measure the drug’s activity against the cancer cells during a 48-hour test. The most effective drugs can then be used to attack the tumor.
Thus far experiments have been carried out on mice and have shown promising results against Triple Negative type breast cancer, which does not respond well to standard treatments. Technion expects to transition to clinical trials within a few years.
Personalization through Fruit Fly Avatars
One creative approach to personalized cancer treatment involves fruit flies. Ross Cagan at Mount Sinai Hospital in New York raises fruit flies that mimic the genetic mutations seen in cancer patients. For a single patient he breeds thousands of flies and then tests them against a “library” of 1,200 different FDA-approved drugs. Some of these are cancer drugs but most are not. Cagan measures which drugs are effective against the personalized fruit fly “avatars,” then recommends a combination for use by the patient’s oncologist.
New Research Models Needed for Clinical Trials
One of the dilemmas of personalized cancer therapy is knowing how to measure its effectiveness. Oncologists need this information to guide the application to other patients, and to justify insurance coverage.
New therapies normally require clinical trials of many patients over an extended period of time to demonstrate increased survival compared with standard treatments. However, the use of personalized cancer therapy means that every treatment is a one-off, not easily comparable with any other. Researchers need improved models for trial studies, so that they can analyze personalized therapies and validate them for application to additional patients.
Personalized Cancer Therapy as the Ultimate Cure
Personalized cancer therapy began with the recognition that cancer is not one disease, but many. Moreover, its manifestation is almost as unique as the individual patient.
That problem, so stated, seems to present impossible challenges. Not only must oncologists validate uncountably many therapies, but they must deliver patient care through a medical system whose success relies on well-specified, repeatable protocols.
Nevertheless, personalized treatment has already made great advances. This success has spurred researchers to invent a continual stream of new approaches, some of which directly address the problems of systematizing individual care. Continued progress holds the hope that personalized cancer therapy will substantially conquer this family of diseases.
Personalized cancer therapy is a logical extension of the ideal of personal medicine: therapy that matches the individual patient. When you see your doctor, to what extent are you receiving personalized treatment, versus being led through a set checklist?
– “Top 10 leading causes of death, 2015” from figure 8 of Health, United States, 2016
– Lead image adapted from “Male And Female Icon” by GDJ on openclipart.org
– The Cancer Genome Data Base allows searching by disease, gene and gene variant to find clinical trials registered with US National Cancer Institute and applicable anti-cancer drugs
– July 2017: Personalized cancer vaccines show glimmers of success
– June 2017: In a major shift, cancer drugs go ‘tissue-agnostic’3
– June 2017: Supply of promising T cell therapy4 is strained
– November 2016: Tiny barcodes provide huge advance in personalized cancer therapy
– April 2015: Series of three articles on Personalized Cancer Medicine: Part 1; Part 2; Part 3