Programmed Cell Death is Key to Determining the Best Cancer Treatment
By Robert Nagourney, M.D.

Functional profiling is a laboratory technique that measures how cancer cells respond when they are exposed to drugs and drug combinations

Modern advances in our understanding of cancer biology have shown that cancers arise from cells that have learned certain tricks to enhance their survival so they can outlive their normal counterparts. 

These transformed (cancerous) cells interact directly with their micro-environment.  Cancer cells "talk" to each other and to all the surrounding cells using chemical signals like growth factors and byproducts of metabolism.  Blood vessels, immune cells and connective tissues all participate and contribute to the cancer process.

To treat a disease that is so complex, hundreds of drugs, drug combinations, and targeted agents are used on patients. With so many choices, how does your oncologist decide which ones are right for you?

Generally, oncologists use established regimens developed through randomized clinical trials to prescribe chemotherapeutic agents. These regimens are average solutions for the “average” patient.

Regrettably, average treatments provide average outcomes, with the majority of patients failing to show significant improvement from these protocols. Drugs that work for one patient may not work for another, even if they carry exactly the same diagnosis.

One way to help identify the best treatment option is for someone to submit a living sample of cancer cells for what is called a "functional profile."

Functional profiling is very different from genomic testing which is offered by most medical centers.  Genomic testing looks for mutations and other changes in each patient's gene makeup that might guide drug selection.  Although the concept is appealing, in reality, a minority of patients have genetic changes that can be used for therapy.

Functional profiling, instead, measures how cancer cells respond when they are exposed to drugs and drug combinations. It is a real-time measure of which drugs cause your cancer cells to die, through a process called programmed cell death.

By using this approach, it can be determined in the laboratory the best drugs for each patient before they receive them.

For example, recently, I received a telephone call from Des Moines, Iowa from a 60-year-old gentleman who had presented with gastrointestinal cancer.

Having the capacity to seek medical opinions from experts around the US, he traveled to Texas to one of the leading cancer centers. His disease was too advanced for surgery so he began a drug combination known as FOLFOX, one that is widely used for his cancer. He remained on treatment until a follow up scan following 4 cycles of the FOLFOX chemotherapy revealed that the disease had progressed in the chest and lymph nodes in the neck.

Although he was at one of the most famous institutions in the country, their second line recommendation, not unlike their first line therapy, was straight out of the textbook, the two-drug combination of Ramucirumab plus Paclitaxel. As he considered his situation, he contacted me to discuss his clinical options.

I explained that he had received appropriate therapy in Texas, but that he had simply not responded. As FOLFOX therapy carries a response rate of 30-50% for his cancer, his failure to respond wasn’t out of the ordinary for this disease.

The recommended 2nd line therapy, though reasonable, was not different from treatments that he might be offered in Des Moines, Sheboygan or Hackensack, New Jersey. Though there was nothing wrong with the second line choice, there just wasn’t anything particularly right about it either.

The patient and his wife decided to travel to California where we conducted a lymph node biopsy.

The surgical procedure led to a complication that required weeks of recovery but when the results of the biopsy were complete, they revealed an unexpected degree of activity for drugs that inhibit a cellular protein known as the epidermal growth factor receptor (EGFR) suggesting that this patient’s tumor might be using this pathway to grow and survive.

Based on these results and further examination of his results from Texas, I pieced together a combination of carboplatin, paclitaxel, and the anti-EGFR antibody Cetuximab that fit very closely with the findings in the laboratory study.

The patient’s response to this combination of drugs was dramatic.

He had begun to eat, the tumor had diminished markedly on PET and CT scan, and he had tolerated the treatment well, though did complain of some neuropathy as a side effect.

As I examined the patient's outcome, I realized that the combination was relatively simple, readily available, generally well tolerated, and something that absolutely no other institution would have recommended. There was nothing particularly difficult about giving the treatment; the real difficulty was identifying it.

The patient's outcome is instructive. First, we were able to identify a smart and relatively well-tolerated, effective treatment. Secondly, we were able to work with colleagues in Chicago, making the patient's life easier.

From the time that the notion of chemotherapy developed in the 1940s and 1950s, and then was put into practice by Drs. Goodman and Gilman at Yale and Dr. Sydney Farber and his colleagues at Harvard in the 1960s, cancer researchers understood two important factors: 1.) Cancer could be treated, managed, and sometimes cured; 2. But at the same time, millions of cancer patients were suffering significant toxicity.

From that time on, the idea of a test to determine the amount and the type of chemotherapy was born. This is sometimes generically called chemosensitivity and chemoresistance assays, or tests. If a patient could be tested in advance and know what was most likely to help, and less likely to harm, we would be much closer to the Hippocratic Oath that says, “First, Do No Harm.”

Throughout the ensuing decades, there have been many excellent researchers working at this – many successfully, some not so much. Unfortunately, some of the failures have been well publicized in medical circles, blunting the excellent work of so many.

Through the decades there have been hundreds of studies that have shown the benefits of functional profiling. Functional profiling can and does increase the odds for cancer patients. As we have shown, using these cell death measures can significantly improve both the likelihood and duration of clinical response for patients found sensitive to drugs and combinations.

The beauty of functional profiling lies in its simplicity, efficiency and close proximity to human biology, unadorned by manipulations that risk adding complexity and cost without benefit.


Dr. Robert Nagourney is an internationally recognized pioneer in cancer research and personalized cancer treatment.

With more than 20 years of experience in human tumor primary culture analyses, Dr. Nagourney has authored more than 100 manuscripts, book chapters, and abstracts including publications in the Journal of Clinical Oncology, Gynecologic Oncology, and the Journal of the National Cancer Institute.

Over the past 20+ years, Dr. Nagourney and his team at the Nagourney Cancer Institute are specialists at functional profiling, which measures how cancer cells respond when they are exposed to a wide variety of drugs and drug combinations.  


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