Clinical and Translational Research: a Strategy

Paolo Comoglio M.D. Scientific Director Clinical and Translational Research

The Institute strategy for the clinical and translational research revolves around three main topics interlocked topics: targeted therapy, molecular diagnosis and cancer stem cells.

“Targeted therapies”
Cancer is a complex disease, associated with genetic lesions (changes in DNA sequence which result in the production of altered proteins) which tend to accumulate over time as a result of exposure to environmental carcinogens, diet and lifestyle.Tumours usually arise in adults because cells in our organism are subjected to continuous attacks which accumulate over the person’s lifespan, damaging the genome, beyond a threshold which leads to “neoplastic transformation”. In this way genetically altered daughter cells develop. They start to proliferate and invade neighbouring tissues in an uncontrolled way.
The fact that tumour cells contain several genetic lesions and that these cells tend to accumulate further anomalies as time progresses, suggests that cancer is a heterogeneous disease which is difficult to attack, also because treatment would have to take place on too many fronts and because of the disease’s continuous evolution inside the patient. However research has made huge and unexpected progress: contrary to initial hypotheses and fortunately for patients, molecular lesions which cause the most widely spread tumours and which feed their growth are not more than a few dozen. This piece of information has driven pharmacology practitioners to undertake a titanic effort to formulate and validate drugs which are able to block the activity of this small set of altered proteins, producing the latest generation of drugs which are being studied today or are already into clinical trials.
These new therapies are called “targeted” because they switch off the function of specific molecules in an extremely selective marnner.
IRCC strategy throughout the next years is to attain important goals within the field of targeted therapy by: (i) identifying pathologies and recruiting patients who will benefit from currently available or novel targeted therapies; (ii) designing and leading clinical trials – within international networks – in a leadership position for the Institute; (iii) developing translational research to conceive novel targeted therapies, where not yet available.

Molecular-based diagnosis
The success of targeted therapies is based on the fact that the molecule targeted by the drug is active - as a result of a genetic lesion - in the tumour but not in the surrounding healthy tissue. Therefore the molecule’s inactivation affects the cancer tissue but should not produce organ-wide damage. This fact has two important clinical consequences: first of all, before subjecting the patient to targeted treatment, the presence of a the genetic lesion which is predictive of the drug’s potential response must be ascertained. In other words, therapy is only effective in those patients whose tumours’ DNA contain the alteration which makes the tumour itself susceptible to the targeted drug. The second implication is that this diagnostic/therapeutic approach inevitably will put into question traditional medical practice regarding neoplastic disease: from the standpoint of targeted therapies, tumours will be no longer classified by location in the body, and/or only by morphological characteristics, but by their molecular anomalies which characterise the relevant genetic lesions, and at the same time render them vulnerable to targeted treatment.
This type of approach entails a gigantic organizational and technological effort which goes from (i) management of biopsy material on which molecular diagnosis is conducted (generating a tissue bank), (ii) the availability of the technologies which are necessary for large scale genetic analysis of patients and (iii) to the development of novel non-invasive molecular imaging techniques.

Cancer stem cells: clinical implications
New discoveries suggest that anti-cancer therapy is truly effective not only when it hits the right molecular target but when it  is active on the small subset of cancer cells that are actually responsible for the cancer growth. Contrary to rather general belief, cancer cells are not all the same; tumours typically contain 90-99% of cells which are relatively harmless and susceptible to conventional therapies (surgery, chemo/radio therapy).  The remaining 1-10% of tumour cells represents the true cause of the disease: unfortunately these cells are very therapy resistant and are capable of regenerating the tumour after traditional therapies have destroyed most of the tumour mass. These cells, capable of surviving anyhow and anywhere, are called “cancer stem cells”,  because they are closely related to the normal stem cells in the organism, which are those that sustain the development of our body during embryogenesis and that enable us to renew worn parts of ourselves during adult life.
The challenge of part of the clinical research undertaken in the Institute is, therefore, to identify the stem cell subpopulation in patients that carry different types of cancers, and to characterize the presence of genetic lesions which make them susceptible to treatment using targeted therapies.
In this novel field of translational and clinical research, IRCC intends to elaborate technologies designed at (i) identifying the subpopulation of stem cells in cancer patients and (ii) characterizing genetic lesions which render this cellular subpopulation susceptible to treatment by targeted therapies.

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