Targeted agents in splenic marginal zone lymphoma: mechanisms of resistance and new combinations

Lymphomas are among the ten most common cancers, primarily represented by elderly subjects. Though management of NHL has witnessed significant improvements, on a EU scale it is estimated that ~190,000 subjects still die from lymphoma each year (3% of all deaths, and ~35% of deaths from hematological cancers). The World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues recognizes splenic marginal zone lymphoma (SMZL) as a distinct clinico-pathologic entity. Though SMZL shares an indolent disease course, it still remains incurable disorder and no consensus exists about the best therapies. The current treatments for SMZL are initially effective in inducing responses in most patients, but they are not curative and show decreasing efficacy with repeated administrations, ultimately resulting in the selection of a chemoresistant clone or in transformation into an aggressive lymphoma. In addition, chemotherapy-based regimens are associated with short and long-term toxic effects, including cumulative myelosuppression, neuropathy, cardiac toxicity, and secondary cancers. Toward the aim of eradicating the disease with the minimum load of toxic effect, the new treatment scenarios of lymphomas will include chemotherapy-free approaches based on the pharmacological inhibition of the pathways to which the disease is addicted. Modern advances in genomics and cancer biology, including our own studies, have produced an unprecedented body of knowledge regarding the molecular pathogenesis of and B-cell lymphoma. In particular, studies performed by the applicants and by others have disclosed a number of cellular pathways that are deregulated in SMZL including NOTCH signalling and NFKB pathway. In parallel to these biological advances, several new classes of molecularly targeted agents have been developed with varying degrees of efficacy across the different types of mature B-cell tumors. In general, the development of new drugs for treating B-cell lymphoma has been mostly empiric, with a limited knowledge of the molecular target, its involvement in the disease, and the effect of the drug on the selection of resistant mutations. Thus, the variability observed in clinical responses likely results from underlying molecular heterogeneity. In the era of personalized medicine, the challenge for the treatment of patients with B-cell lymphoma will involve correctly matching a molecularly targeted therapy to the unique genetics of each individual tumor. Through the use of innovative tools and approaches for the generation of biomedical data, including "-omics", high throughput, the project will address three major unmet clinical needs in the field of new targeted drugs treatment of SMZL, and of other B-cell lymphomas as well, namely: i) unraveling molecular mechanisms of resistance to new compounds that are in clinical development; ii) identifying accessible and highly sensitive biomarkers for the early detection of targeted drug resistance in patients; and iii) developing of targeted drug combinations to overcome the entire tumor and avoid the selection of resistant clones. The ultimate goal of the project is making biomarker-driven personalized medicine a reality in the management of B-cell lymphoma.A fast and efficient transferability to the clinical setting of the results of this project will be granted by i) the multidisciplinary attitudes of the applicants; ii) the vocation of IOSI to the early clinical development of new anti-cancer treatments; iii) the interconnection of the applicants with a multi-institutional research network in the field of CLL and other B-cell tumors; and iv) the tight collaboration of the applicants with Swiss Group for Clinical Cancer Research (SAKK) and the International Extranodal Lymphoma Study Group (IELSG).