Cell biologists from BIOCEV pointed out the limits of the Cancer Moonshot Initiative (9.1.2017)

The New England Journal of Medicine is among the most prestigious peer-reviewed biomedical journals with current impact factor 59.558.

Members of the Department of Cell Biology, Charles University and BIOCEV, Jan Brábek and Daniel Rosel recently published in New England Journal of Medicine a Letter to the Editor, which points out the limits of global anti-cancer initiative called Cancer Moonshot.

The article refers to failure of clinical trials in solid cancer which were based on Precision Medicine (SHIVA, Battle-2), explains the reasons of the failure and suggest fundamental changes in the strategy of global anti-cancer initiative, led by former vice-president of United States Joe Biden (Cancer Moonshot).


Interview with Professor Jan Brábek:

From your letter it is concluded that you are not in favour of precision medicine (PM). Is this correct?

Jan Brábek: We are in favour of the recognition of the importance of anticancer research. But in view of recent PM trial results, namely, SHIVA and Battle2, we suggest a rethink of strategy. Here, we fully support the Sounding Board by Professors Ian Tannock and John Hickman. Reasonable folks would agree with Albert Einstein who said that repeating the same experiment and expecting a different result may be futile.


What do you propose?

We propose an alignment between preclinical science and clinical outcomes, since new drug discovery is best directed to interrupting the natural history of solid cancer – local invasion and metastasis.

Currently, approval criteria by regulatory agencies are based primarily on tumour shrinkage, which does not reflect nor predict the development of metastasis. In solid cancer, greater than 90% of mortality results from metastases. New imaging technologies have the potential to track the metastatic cascade, and could be developed as clinical evaluator criteria, and as an alternative to size-based schemes. You may recall that size-based schemes were introduced about 40 years ago and were useful in quantitating the effect of cytotoxic drugs. Much progress has been made in science and medicines, and size-based schemes like RECIST, are not suitable for many novel classes of anti-cancer drugs. (Fernandes M, Rosel D, Brábek J. Translation in solid cancer: are size-based response criteria an anachronism? Clin Transl Oncol. 2015; 17(1):1-10.)

Today, patients and their families are more concerned about the “M” word than the “C” word. Scientists, oncologists, and regulators should be listening and acting.


Could you suggest a few novel approaches?

We are cell biologists and based on the expected responses to our letter, we are working on a follow-up publication directed to your question and incorporating suggestions made in response to our letter in the N Engl J Medicine January 5, 2017.

A collaboration between scientists, oncologists, radiologists, and regulators is a prudent approach. In the interim, we could direct you to imaging authorities, Tom Yankeelov at the University of Texas/Austin, David Mankoff at the University of Pennsylvania, Kay Pepin and Richard Ehman at the Mayo Clinic.


The assumption on PM was that genomics would revolutionize medicine. Why has it taken till now for this flaw to be recognized?

We are not the first. Sixteen years ago, Neil Holtzman at Johns Hopkins, Baltimore, and Theresa Marteau at Cambridge University, UK, questioned this approach (Holtzman NA, Marteau TM. Will genetics revolutionize medicine? N Engl J Med 2000; 343: 141-44). Their concerns are still valid today.

Today, two well designed and well conducted clinical trials to evaluate the utility of precision medicine in solid cancer have failed, namely, SHIVA (France) and Battle-2 (USA). Under the guidance of Moliere, the explanation is that the precision medicine initiative has been a huge success; the poor outcome is due to drug resistance. Proposals aimed at using the same approach with combination therapy in order to negate drug resistance have a high probability of both being funded, and resulting in failure.

This under-thought strategy is in keeping with the “Whack-a-Mole” game seen in state fairs in the USA. The continuing popularity of this game is inexplicable; there are no winners – the mole (drug resistance) always pops back!


Finally, do you have any advice for decision-makers?

Recognizing and supporting R&D towards critical unmet need is responsible policy. But it is best for scientists and oncologists, not politicians, Information Technology, nor regulators, to lead the way forward. In the case of precision medicine, there was no debate. The message from high was simple and clear: fall in line, or lose funding.

In uncertainty, diversity in approach is prudent, and a single untested theme risks not only failure, but has the potential to undermine comprehensive research in cancer. In the current situation students, junior, mid-career, and senior scientists in cancer-related but nongenomic disciplines face an existential problem related to recognition and support. If the title or even keyword of their proposal does not include “precision medicine” the chances of being funded is much lower.

What we do need is safe, effective, and affordable medicines for solid cancer. Much progress has been made in stromal/microenvironment-directed initiatives that are focused on common denominators of the disease, namely, the role of hypoxia, ECM structural changes and degradation, desmoplasia/fibrosis. The problem with a fixation on unique mutations is that they are moving targets; drivers become passengers and vice versa. The tissue microenvironment, not the cancer cell, is the decision making unit for launching the metastasis cascade. (Brábek J, Mierke CT, Rösel D, Veselý P, Fabry B. The role of the tissue microenvironment in the regulation of cancer cell motility and invasion. Cell Commun Signal. 2010; 8:22).

We are also driving a novel approach – Migrastatic drugs. This new class is directed towards an antiinvasive, antimetastatic objectives, and the focus is on inhibiting directed motility. As designed, these agents will not cause tumour shrinkage, and will therefore not be approvable based on current regulations. However, we have to keep in mind, that morbidity and mortality in solid cancer is primarily the result of metastasis and not tumour enlargement. Benign tumours, despite increased size, do not kill.

Petr Solil
Head of Communications, BIOCEV


About the group:

Laboratory of Cell Invasion in Cancer

We are cell biologists with long term interest in molecular and cellular mechanisms of cancer cell invasiveness. Currently we are mostly concentrated on plasticity of cancer cell invasiveness and approaches to fully inhibit the invasiveness of cancer cells in 3D environment. Invasiveness is a critical prerequisite for formation of metastases, which are responsible for 90% deaths in solid cancer. To find out effective, but also affordable (Brábek and Fernandes, The Lancet Oncology, 2011) ways to inhibit cancer cell invasiveness is therefore critical for improving survival of patients with solid cancer.

We believe that concentration on invasiveness and stroma/cancer metabolism is a valuable alternative to precision medicine based approaches since the targeting of these processes is effective even under the conditions of tumor heterogeneity and is expected to be much less costly (Fernandes, Rosel and Brábek, New England Journal of Medicine, 2017).

In this scientific journey we came into contact with leading scientists all over the world from areas of medicinal chemistry, translational oncology and clinical imaging to develop the novel ways of metastasis diagnostics, prevention and pragmatic treatment based on natural history of disease and rational endpoints.

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