The Young Lions — Harnessing Next Generation Technologies to Help Current Cancer Patients and the Oncologists Who Treat Them

Based on our published works in Cancer Discovery and editorials in Nature and Nature Medicine

By Carla Grandori, MD, PhD — Founder / CEO SEngine Precision Medicine

November fourth will always be a solemn and prideful day for me. Like so many who have lost loved ones to cancer, this is a day marked by looking at old photographs and re-reading yellowed letters. They bring my grandmother, Nonna Gina, to life again. She was a dedicated 1950’s biologist who inspired me to pursue my passion for science. She passed away from stomach cancer on November 4, 1976.

Her suffering was made all the more painful by unwarranted chemotherapy. The seed, which began my life’s work searching for targeted, effective, and less-toxic cancer therapies, was planted that November day.

I remember how, when I was a child, my grandmother would point to a poster in her study of two beaming men with a distinguished, even whimsical, aura. “Do you see those two men?” my Nonna would ask, then explain, “They are Francis Crick and James Watson. In 1953 they were the ones who discovered DNA, explaining how our genes are transmitted and work. They won the Nobel Prize! They are the young lions of science. Their discovery will revolutionize medicine!” Then she would lean in and whisper, “But remember, it was Rosalind Franklin who provided the photographs of DNA that helped them solve the puzzle.”

She may have been the only Nonna in Milan with a poster of Crick and Watson on her wall. I never forgot the poster or her inspiring words about Crick, Watson, and Franklin. I also remember words she spoke to me from her hospital bed that November as the slow drip of orange medicine, likely doxorubicin, was making her sick. “Carla, as you are choosing your path, think about the discovery of Watson and Crick. It will revolutionize how we practice medicine. Perhaps you will find a better way.”

Now, sitting in my office at SEngine Precision Medicine, I find myself flanked by posters of my own. While my grandmother had posters of heroes, I find myself staring at their ultimate villains — the red and blue tessellated representation of ovarian and breast cancer genetic landscapes. The images lay bare a complex series of coded clues.

Unlike the improbable hope one pill will cure cancer, these images do not present a single vulnerability. Rather the clues to treat cancer are specific to multiple forms of cancer and multiple vulnerabilities. Just as no two people are identical, neither are any two cancers identical.

Gone is the simplistic idea that a single pill can cure cancer. Our treatments must adapt.

I am emboldened by a photograph on my desk, which would no doubt have filled my grandmother with pride. It was taken at a meeting in China, the first of several encounters and scientific exchanges with Dr. Jim Watson. At the moment I asked Dr. Watson the question, “Would you rather know the DNA sequence of your cancer or know how to kill it?”

He responded, “That’s a no brainer, I’d rather know how to kill it.”

Over the years, my conversations with Dr. Watson have distilled into a single question: How do we move beyond merely sequencing a cancer’s DNA to identifying and targeting its precise weaknesses?

It is this question that has grabbed hold me of me and will not let me go. And it is the question my fellow researchers at SEngine and I ask each time we receive a living sample of someone’s cancer cells. While several laboratories around the country now work by culturing living cells, in fact, SEngine is the only laboratory in the country that is Clinical Laboratory Improvement Amendments (CLIA) Certified to test hundreds of drugs on solid tumors. In summary what we do is precision medicine, but with a twist, referred to “Functional Precision Medicine.”

Very recently hundreds of scientists, including myself, contributed to compiling and interpreting The Cancer Genome Atlas (TCGA). Our new young lions of science are the ability to couple this descriptive information obtained from sequencing DNA with functional testing. Only together do they yield actionable results for cancer patients and new drug targets for pharmaceutical companies to provide ever more effective treatment options.

The technology we’re employing in my lab at SEngine Precision Medicine makes it possible for us to accelerate the search for cures. It is a form of robotic technology referred to as high-throughput screening. To get a picture of this, you might begin by supposing that, instead of testing cells in a single petri dish, we are using a 400-well ice cube tray. Our advanced robotics tests each well. SEngine’s technology is capable of performing thousands of miniaturized experiments on a 3D clone of patient’s cancer every minute — producing significant discoveries and life-changing results.

We named this test the P.A.R.I.S. Test after the mythical hero who defeated the undefeatable Achilles by aiming at his only weakness. Similarly, our P.A.R.I.S. Test aims to precisely identify the unique drugs for each individual cancer, rather than blindly throwing darts as time and lives slip away. Every day we are discovering a growing number of targeted drugs, and identifying those drugs that do not kill a broad range of tissues, but only kill those targeted genes that are essential for the survival of cancer cells.

During a panel discussion late last year at the New York Stem Cell Foundation, I spoke about cataloging the important information gathered from live biopsies of solid tumors (ex vivo cancer models) from hundreds of patients in a living database. Such a living database will eventually allow us to decode the complex mosaic of each unique cancer into a road-map for cancer cures.

If you are a cancer researcher or oncologist and reading this, you may be familiar with our work published throughout the years. However, it was only last year that the first demonstration of the approach was employed to personalize treatments. This was also demonstrated in our collaborative study, published in Cancer Discovery:Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine” by Chantal Pauli et al.

My team at SEngine, and at our non-profit organization Cure First, recently used high through-put screening to test more than 100 FDA-approved drugs against four different tumor organoids. We reconfirmed the startling truth: cancer is exceptionally personal. As evidence, during our screen, we found four different combinations of drugs that would work best for each of the four patients.

If you are reading this and you are a cancer patient, or the loved one of a cancer patient, this information is both empowering and heartbreaking. It is empowering because it means, as our research shows that your cancer could potentially respond to a discreet drug or to a combination of drugs that are approved for other cancer types and entail less-toxic options then classic chemotherapeutics. This is what allows us to answer the question our patients commonly ask: Can you find a drug that will work for my cancer? This information may also be frustrating because this could be the first time you are reading of this advance in diagnostic options.

There are more articles that I would encourage you to read and use to inform yourself about functional precision medicine. The study Dr. Pauli published in Cancer Discovery has subsequently been discussed in the July 2017 publications of Nature and Nature Medicine.

The photo of Dr. Watson and myself continues to remind me of the significance of our conversation — one that continues today. Thanks to the research cited above, and our new pride of young functional precision medicine lions, we can discover vulnerabilities in each patient’s unique cancer.

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