AIRC Special Program in Clinical Molecular Oncology

On 16 September 2009, AIRC (the Italian Association for Cancer Research) presented the Special Call for Research Proposals in Clinical Molecular Oncology – the so-called 5‰, which envisaged the kick-off of five Programs, with overall funding in the range of 50 to 75 million euros, based on the requirements contained in each individual request. The Program is economically viable thanks to the financial resources that come from the 5‰. The 5‰ is a voluntary contribution, on behalf of each participating Italian tax payer, of 5 thousandths of their yearly tax return, to a registered charity of their choice, such as AIRC.

Today, seven months later, five Programs have been chosen by a commission of eighteen international review panel members. The researchers who will guide them are: Federico Caligaris-Cappio, Paolo Comoglio, Roberto Foà, Alessandro Massimo Gianni, and Alessandro Vannucchi. In total they will coordinate the work of 464 clinicians and basic scientists.

AIRC makes available, for the five year duration of this project, 60 million euros, funding in full the requests that the researchers have submitted.

The Special Program in Clinical Molecular Oncology answers the call of those who have donated their 5‰ to AIRC, and would like to see more effective cures for cancer in the near term. The translation of research results into clinical procedures of real benefit to the patient makes up one of the most substantial problems for the whole medical field and for oncology in particular. It is not easy because it requires the integration of two worlds – the clinic and research – which speak languages that are in part different. However, the best interests of the patient are paramount and so a creative effort, a will to succeed and economic support are indispensable.

The five funded Programs fully answer the call for research proposals’ primary requirement: to actually transfer new molecular know-how, acquired in the laboratory, to the patient, within the duration of the project. The activity will take place in two phases: a first three-year period, at the end of which the reviewing commission will carry out a site visit, to check that the expected objectives have been achieved. Only if that visit has a positive outcome, will the Program complete its full five-year term.

An indispensable requirement which is common to the projects is: the presence of a group leader who has good competence in the areas of molecular oncology, pathology and clinical oncology, and is capable of guiding a multi-disciplinary team.

The eighteen international review panel members are clinicians and basic researchers who are top-level leaders in the oncology field. They represent the preeminent oncology institutions in the world. The selection of projects occurred in several stages. In the first step, the reviewers chose from the 30 preliminary proposals received in November 2009. Subsequently the competition was narrowed to 11 candidates who then submitted a full proposal in February 2010. The best five projects were funded.

The Programs were judged to be of a high scientific standard and the reviewers also remarked on the extraordinary quality of Italian research groups. Robert Bast, Vice President of Translational Research at the M. D. Anderson Cancer Center in Houston, Texas, who is coordinator of the reviewing Commission, commented: “We were deeply impressed by the quality of the proposals and by their potential to improve cures for cancer patients. The many programs that we selected attest to the excellence of Italian translational cancer research”. It was therefore extremely complex for the reviewers to select the best five Programs, as envisaged by the call for proposals, that should receive financial priority.

The Institute for Cancer Research and Treatment (IRCC – Candiolo) was awarded the largest grant, worth 9,080,000 euros for the first three years, renewable to the full five year duration.

Paolo Comoglio,MD, director of translational and clinical research at the Institute, is the head of a project that was conceived some time ago. This project is focused on the natural clinical development of basic research that began 20 years ago, which brought about the discovery of genes that control “invasive growth” signals, whose archetype is the Met oncogene. This research – which has been taking place without interruption – started with molecular genetics, passed through biology and experimental pathology, and has more recently come to diagnostics and molecular therapy. These efforts focus on colon carcinomas that are resistant to conventional therapy. The time it has taken, and the information collected so far, now allow us to leap ahead toward “targeted therapy”. It is reasonable to suppose that results will reach the patient within the time-span of this project. To this end, a training and recruitment program has been started, in order to form a cadre of Clinical Research Assistants, who will divide their efforts equally between the laboratory and the patient’s bedside. The number of people involved approaches one hundred and is structured into 11 research groups, of which 1 is extra-mural (Niguarda Ca’ Granda Hospital, Milan)

The IRCC Project:

“TARGETING RESISTANCES TO MOLECULAR THERAPIES
IN METASTATIC COLORECTAL CARCINOMAS”

Abstract
Colorectal cancer (CRC) is the second commonest cancer worldwide and the metastatic disease accounts for 40 to 50% of newly diagnosed patients. Despite therapeutic advances, the prognosis for patients with metastatic CRC (mCRC) remains unfavourable, with a median overall survival of 18 to 21 months. In unselected patients, addition to chemotherapy of monoclonal antibodies against the epidermal growth factor receptor (EGFR) – the golden standard targeted therapy – results in a modest improvement in median progression-free survival (less than one month) and response rate (5-8% more than chemotherapy alone). When used as monotherapy, the anti-EGFR antibodies are effective in only 10-15% of patients. It is now well established that colorectal tumours carrying KRAS and BRAF activating mutations (40%) are refractory to EGFR targeted therapies (primary resistance). Among the remaining KRAS/BRAF wild-type patients (60%), the responders are less than 20%. Finally, all responsive patients eventually become insensitive to anti-EGFR antibodies (secondary resistance). Both primary and secondary resistances are due to genetic lesions that drive oncogenic hyperactivation of collateral signalling pathways. For example, amplification of the MET oncogene has been recently implicated as a mechanism of resistance in lung cancers treated with EGFR small molecule inhibitors.

In CRC, MET is frequently hyperactive and triggers a number of signalling pathways superimposable to those triggered by EGFR, suggesting that MET could be a driver of resistance in mCRC as well. An alternative (or complementary) possibility is that relapse could be due to the emergence of a preexisting cellular population that is intrinsically drug-insensitive, a unique feature of cancer stem cells (CSCs). Notably, CRCs contain a stem cell compartment, and cancer stem cells from CRCs express active forms of MET.

The overall poor outcome of therapies targeting EGFR parallels the weak efficacy of anti-angiogenic drugs. Addition of anti-VEGF to anti- EGFR antibodies worsens progression-free and overall survival of mCRCs. In its essence, this ‘escape’ from anti-angiogenic treatment is again a form of resistance; it involves multiple adaptive mechanisms that include, among others, MET upregulation and MET-induced dissemination of cancer cells out of hypoxic areas. All these issues severely restrain the clinical effectiveness of targeted therapies against mCRCs. This proposal aims at tackling such limitations in order to optimise patient selection and increase response rates, two unmet medical needs that still await rational implementation. We intend to (i) identify novel response biomarkers; (ii) investigate the molecular mechanisms of secondary resistance; (iii) evaluate whether resistance involves selective expansion of the CSC compartment; and (iv) explore new therapies for resistant mCRCs. The longstanding experience of the Institute in the basics of the MET oncogene will be translated into preclinical and clinical research. We will focus on the potential role of this oncogene as a causative agent of resistance to EGFR-targeted therapies, escape from anti-angiogenic therapies, and expansion of CSCs. To achieve these objectives we will exploit innovative experimental and clinical approaches, including: (i) trials ex vivo in ‘xenopatients’ (in which animals bearing tumours from individual patients are monitored for clinical response, relapse, and progression); (ii) the use of isogenic cell lines (in which drug-sensitising or drug-resistant cancer mutations have been ‘knocked-in’ by somatic homologous recombination); (iii) ethically approved, biopsybased clinical trials (in which tumour tissue is biopsied before and after development of secondary resistance). Ultimately, we will design ad hoc clinical trials, aimed at improving personalised treatment. The final output will be the direct translation of all this information into a superior armamentarium of therapeutic regimens to treat metastatic CRC patients resistant to “state-of-the-art” molecular targeted therapies.

LIST, AFFILIATIONS AND COMPETENCES OF THE PARTICIPANTS

Principal investigator:
Paolo M. Comoglio, Scientific Director, IRCC, Candiolo

Clinical Coordination Unit:
Silvia Marsoni, Director, Clinical Coordination Unit, IRCC, Candiolo
and Director, Southern Europe New Drug Organization (SENDO), Milano

IRCC Integrated Core Services:
Daniele Regge, Director, Imaging Unit, IRCC, Candiolo
Mauro Risio, Director, Pathology Unit, IRCC, Candiolo
Antonio Sottile, Clinical Chemistry Unit, IRCC, Candiolo
Teresio Varetto, Director, PET-Nuclear Medicine Unit, IRCC, Candiolo

Group Leaders

Task 1: Analysis of positive predictors for EGFR-targeted therapies in mCRCs: an ex vivo prospective trial in ‘xenopatients’
Livio Trusolino, Laboratory of Molecular Pharmacology, IRCC, Candiolo: coordinator
Alberto Bardelli, Laboratory of Molecular Genetics, IRCC, Candiolo: genetics
Enzo Medico, Laboratory of Oncogenomics, IRCC, Candiolo: transcriptomics
Salvatore Siena, Falck Division of Oncology, Ospedale Niguarda Ca'Granda, Milano: clinical oncology
Massimo Aglietta, Division of Medical Oncology, IRCC, Candiolo: clinical oncology
Michele De Simone, Division of Surgical Oncology, IRCC, Candiolo: surgical oncology

Task 2: Hypothesis-driven therapies to overcome primary resistance to EGFR-targeted agents: a preclinical approach in cell lines and xenopatients
Alberto Bardelli, Laboratory of Molecular Genetics, IRCC, Candiolo: coordinator
Livio Trusolino, Laboratory of Molecular Pharmacology, IRCC, Candiolo: xenopatients
Massimo Aglietta, Division of Medical Oncology, IRCC, Candiolo: clinical oncology
Salvatore Siena, Falck Division of Oncology, Ospedale Niguarda Ca' Granda, Milano: clinical oncology
Michele De Simone, Division of Surgical Oncology, IRCC, Candiolo: surgical oncology

Task 3: Challenging the MET oncogene as a resistance biomarker in EGFR-targeted therapies
Silvia Giordano, Laboratory of Molecular Biology, IRCC, Candiolo: coordinator
Livio Trusolino, Laboratory of Molecular Pharmacology, IRCC, Candiolo: xenopatients
Alberto Bardelli, Laboratory of Molecular Genetics, IRCC, Candiolo: genetics
Salvatore Siena, Falck Division of Oncology, Ospedale Niguarda Ca' Granda, Milano: clinical oncology
Massimo Aglietta, Division of Medical Oncology, IRCC, Candiolo: clinical oncology
Michele De Simone, Division of Surgical Oncology, IRCC, Candiolo: surgical oncology

Task 4: Cellular, animal, and patient analysis to understand secondary resistance to EGFRtargeted agents
Maria Flavia di Renzo, Laboratory of Cancer Genetics, IRCC, Candiolo: coordinator
Livio Trusolino, Laboratory of Molecular Pharmacology, IRCC, Candiolo: xenopatients
Salvatore Siena, Falck Division of Oncology, Ospedale Niguarda Ca' Granda, Milano: clinical oncology
Massimo Aglietta, Division of Medical Oncology, IRCC, Candiolo: clinical oncology
Michele De Simone, Division of Surgical Oncology, IRCC, Candiolo: surgical oncology

Task 5: Colorectal cancer stem cells and resistance to targeted therapies
Carla Boccaccio, Laboratory of Cancer Stem Cell Biology, IRCC, Candiolo: coordinator
Livio Trusolino, Laboratory of Molecular Pharmacology, IRCC, Candiolo: xenopatients
Salvatore Siena, Falck Division of Oncology, Ospedale Niguarda Ca' Granda, Milano: clinical oncology
Massimo Aglietta, Division of Medical Oncology, IRCC, Candiolo: clinical oncology
Michele De Simone, Division of Surgical Oncology, IRCC, Candiolo: surgical oncology

Task 6: Overcoming acquired resistance to anti-angiogenic therapy by inhibiting hypoxia-induced tumour cell motility
Paolo Michieli, Laboratory of Experimental Therapy, IRCC, Candiolo: coordinator
Federico Bussolino, Division of Vascular Biology, IRCC, Candiolo:in vitro and in vivo models of angiogenesis
Livio Trusolino, Laboratory of Molecular Pharmacology, IRCC, Candiolo: xenopatients
Salvatore Siena, Falck Division of Oncology, Ospedale Niguarda Ca' Granda, Milano: clinical oncology
Massimo Aglietta, Division of Medical Oncology, IRCC, Candiolo: clinical oncology
Michele De Simone, Division of Surgical Oncology, IRCC, Candiolo: surgical oncology

Task 7: Translating molecular evidence: hypothesis-driven trials in patients with mCRC
Salvatore Siena, Falck Division of Oncology, Ospedale Niguarda Ca' Granda, Milano: coordinator
Massimo Aglietta, Division of Medical Oncology, IRCC, Candiolo: clinical oncology
Michele De Simone, Division of Surgical Oncology, IRCC, Candiolo: surgical oncology.

Left to right, top to bottom:
F.Bussolino, D.Regge, F.Leone, M.Aglietta, A.Sartore-Bianchi, F.Montemurro, R.Ponzone, A.Bardelli, A.Cassingena, E.Giraudo, E.Medico, A.Bertotti, M.De Simone, A.Amatu, P.Massucco, D.Gramaglia, S.Siena, T.Varetto, L.Trusolino, M.Bruno, P.Gabriele, A.Cignetto, Tabui   (Setter Gordon), S.Giordano, F.De Bacco, P.Comoglio, S.Marsoni, R.Schiavo, F.Di Nicolantonio, MF.Di Renzo, C.Boccaccio

Programma di Oncologia clinica molecolare 5 per mille

Rassegna stampa

Fondamentale - Giugno 2010

^Top.