Microenvironment and Genes in Cancers of the Blood (MAGIC)

Heads: Paolo Ghia and Giovanni Tonon

Vision

Recent breakthroughs in cancer research have reinforced the view that any progress toward the cure of cancer arises from a deep understanding of their pathogenesis. Blood cancers arise when cells reproduce unrestrainedly due to genetic abnormalities in multiple genes that control cell division, differentiation, survival or programmed cell death. On the other side, it is emerging that the tumor microenvironment provides critical stimuli conferring to malignant cells a growth advantage and an extended survival. Causal genes and the microenvironment concur to shape the ultimate phenotype of individual patients, i.e. their clinical presentation, natural history and drug resistance.
In this program, we focus on B lineage neoplasias, as the interaction between genetically abnormal malignant cells and a dysregulated microenvironment is crucial in the pathogenesis of these malignancies, with a focus on acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Non-Hodgkin Lymphomas (NHL) and multiple myeloma (MM). Despite major therapeutic advances, all these tumors are presently incurable. We argue that effective and ultimately curative therapies for these diseases could only emerge from targeting simultaneously the tumour cell its microenvironment interactions.

Goals

The specific aim of the proposed program is to understand the basic biological mechanisms of blood cancers and translate the findings into clinical reality thereby improving both diagnosis and treatment. To this end the proposal is built around four tasks, focused on:

  • Novel therapies.
  • Optimizing existing therapies and improving quality of life.
  • Novel targets.
  • New cellular protagonists.

The aims of Task 1 are to perform preclinical studies on promising in-house compounds to preclinically validate targets and compounds emerging from the other programs and to translate these tools into phase I/II clinical trials. Moreover, we plan to develop, validate and apply molecularly-defined prognostic and predictive markers that will be used to design strategies for personalized treatment. The aims of Task 2 are to optimize existing treatments sparing toxicity and to target the major complications, thereby improving the patients’ quality of life. Task 3 and 4 are more exploratory and are conceived to fuel Programs 1 and 2. Task 3 aim is to address the significance of novel dysregulated or mutated molecules present on the tumor cell surface, through which proliferation and apoptosis signals triggered by cross talk with the microenvironment are conveyed inside the cell. The aims of Task 4 are to thoroughly investigate the relative contribution of different non-tumoral cell types and their mechanisms including some that, due to technical constraints or conceptual limitations, have not been examined in the past.

Main achievements (updated 2012)

Our translational Programme is focused on unmet medical needs in specific hematological cancers and aims at developing and bringing to the clinic fully validated tools to be ultimately implemented in phase I clinical trials. The data so far obtained lead us to believe that we are ready to propose a number of options to the scientific community which may have very rapid clinical translation both as prognostic/predictive factors and as new treatment approaches.
Specifically we have achieved three main conclusions, the first two straightforwardly transferable to clinical application, the third being more exploratory but still very exciting and worth pursuing.
The first conclusion is that chronic hematological neoplams have to be framed within a dynamic Microenvironment-oriented perspective whereby active microenvironments co-evolving with the leukemic clone actively promote disease progression and ultimately support the evolution of more aggressive subclones. The key role of active microenvironments acquires a clinical relevance especially in the present era of non-genotoxic drugs.
The second conclusion is that the stratification of cancer patients based upon gene/microenvironment interactions may lead to more adequate treatment strategies for specific categories of patients.
Indeed, the extensive knowledge amassed in the past decades on the genetic lesions underlying tumor cells has not led so far to more effective therapies, targeting specific genetic subgroups.
The third conclusion is that our overall strategy aiming at unravelling the interaction between cancer cells and their environment has led to the identification of new promising therapeutic targets as well as the potential therapeutic significance of some accessory cell populations that warrant further exploitation and preclinically validation.