Three Nerviano Medical Sciences molecules at ASCO


Nerviano, 2nd June 2008 - Three new anticancer molecules, the result of research by Nerviano Medical Sciences (NMS), are presented in these days at the American Society of Clinical Oncology (ASCO) Conference, being held in Chicago from 30th May to 3rd June.

For these three new compounds the scientists' attention will be called to the results of the phase I clinical trials. Now that PHA 848125, PHA 739358and nemorubicin, the three original NMS molecules, have shown their activity in experimental tumour models in vitro and in vivo, these have now, in fact, progressed to the clinical development phase.
"As far as the first two compounds are concerned, these are molecules with a specific action against molecular targets that have a crucial role in the development and progression of tumours. They therefore fall into the category of what are defined as targeted therapies", explains Francesco Colotta, Director of Oncology R&D.
Their therapeutic potential is considerable as regards solid tumours. In the case of nemorubicin, on the other hand, this is a treatment that interferes directly with tumour cell DNA replication, developed for very specific therapies such as the local treatment of liver cancer.
PHA 848125 is an orally active inhibitor of the kinases CDK2, CDK1, CDK4 and TRKA. Its efficacy in humans is being investigated at two prestigious centres in the United States, where the doses for use in the phase II clinical trials have already been identified. "In phase 1 studies on patients with advanced or metastatic solid tumours, the molecule determined a prolonged disease stabilization phase in two subjects, one with non small cell lung cancer (NSCLC) who received 12 cycles of treatment, and the other with carcinoma of the colon, still on treatment after 16 cycles", says Colotta. At the dose of 150 mg per day, chosen for continuation of the clinical trial, the undesirable effects were mild to moderate, easily managed clinically, and reversible.
"In addition to a first treatment protocol that has already been identified, a second administration plan is being investigated, again using the oral route", continues the expert. The action of PHA 848125 has been chosen for oral discussion among some 22,000 works sent to the United States convention.
For PHA 739358, ASCO will see the presentation of the phase I studies both with and without haemopoietic therapy with G-CSF, the granulocyte colony-stimulating factor.
"The new compound belongs to the class of Aurora kinase (AK) inhibitors involved in cell cycle progression and in oncogenesis that are, in fact, overexpressed in tumour cells, on which researchers worldwide are concentrating their studies", explains Colotta.
"Nerviano Medical Sciences has a prestigious record in this field: it is the first centre in the world to have brought an AK inhibitor to the clinical trial phase", points out the Managing Director of NMS, Giampiero Duglio.
In the phase I clinical trials, PHA 739358 was administered intravenously to 50 patients with advanced solid tumours and in progression of disease. For 10 of these, stabilization of the neoplasm was observed following treatment with the new molecule, which lasted for more than 6 months in 5 cases, including carcinoma of the kidney, oesophagus, ovary, colon and non small cell lung cancer ( (NSCLC).
The level of toxicity, at the dose identified for the phase II studies (330 mg/m2) for a 6-hour infusion, was mild to moderate, easily managed clinically, and reversible.
"These phase I studies with PHA 739358 have been chosen by the Scientific Committee of ASCO for discussion at the session Clinical Science Symposium, which is one of the most important moments of the United States convention", adds Duglio.
Other phase I trials with the molecule, administered in combination with G-CSF to prevent haematological toxicity, will be discussed at the session dedicated to oral presentation of the posters.
The treatment with PHA 739358 +/- G-CSF has been used as a 24-hour intravenous infusion in 56 patients with advanced or metastatic solid tumours. The doses identified for the phase II clinical trials were 500 mg/m2and 750 mg/m2. Haematological toxicity (neutropenia) was prevented thanks to the administration of G-CSF, while non-haematological toxicity was mild to moderate, easily managed clinically, and reversible. "A patient with metastatic small cell lung cancer (SCLC) showed a partial response to the treatment (a 77% reduction in one lesion and the disappearance of another lesion), while clinically relevant disease stabilization (> 3 months) was observed in 9 patients treated with the molecule", states Colotta. The AKs (A, B, and C, the latter less characteristic as regards tumour etiopathogenesis) play a crucial role in cell division (mitosis) and are expressed abnormally in many types of tumour. Furthermore, Aurora A is an oncogen.
These molecules have been identified as the molecular target of new anticancer therapies. One of their effects in experimental tumour models is the inhibition of histone H3 phosphorylation, a reaction that occurs during the course of cell replication and that is mediated by Aurora B kinase. This event, initially observed in pre-clinical studies, has also been confirmed in studies in humans.
In skin biopsies on patients treated with PHA 739358 in phase I trials, a significant reduction was observed in histone H3 phosphorylation. "This observation favours the validity of the initial rationale for the development of AK inhibitors and shows that there is a correlation between the antitumour action observed in humans and AK inhibition", states Colotta. At ASCOnemorubicin will also be discussed: "A new compound that acts directly on tumour cell DNA, intercalating with the bases that make up the primary unit, inhibiting the action of various enzymes involved in cellular proliferation and in the repair of damage to this nucleic acid", explains the Managing Directory of the Oncology BU.
The data will be those obtained from the European phase I study, in which nemorubicin was administered in combination with cisplatin to patients with liver cancer (hepatocellular carcinoma). "This is a local treatment to the liver in patients with inoperable tumours and in whom previous therapies in situ have already proved unsuccessful", the scientist explains. The phase I trials have made it possible to identify the dose to use in the subsequent phase II studies.
"Seven patients showed a response to the treatment with a reduction in the tumour masses in 6 cases and the disappearance of the tumour lesions in one case, while another 6 showed prolonged disease stabilization", explains Colotta.

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