Research projects

The main aim of PREMAMM is to develop a new precision medicine program in multiple myeloma (MM) aimed to identify specific metabolic vulnerabilities, predict synthetic lethality and response biomarkers by the integration of transcriptome analysis and clinical data of a large cohort of 800 mm patients with a computational method recently described by our group and validated in myeloma patients. PREMAMM will not only identify new targets in myeloma but, based on specific genomic abnormalities, will identify individualized patient specific targets, thus providing the grounds for individualized therapy. Validation of patient specific target will be performed using in vitro and in vivo experimental models of myeloma that reproduced the heterogeneity of the disease.

Objective 1. Metabolic landscape of Multiple Myeloma. Using RNA-seq data from the COMMpass cohort of MM patients, together with machine learning and clustering techniques, 6 metabolic groups were identified in MM, clearly associated with relevant clinical-genetic biomarkers of this malignancy. These metabolic groups were validated in other patient cohorts beyond COMMpass.

Objective 2. Computational prediction of metabolic vulnerabilities in MM, patient stratification and selectivity. Using RNA-seq data discussed above, we have developed a predictive model of metabolic vulnerabilities and proposed different therapeutic targets and associated response biomarkers in MM. In particular, we are currently analyzing the role of 2 genes: UAP1 y CTPS1.

On the other hand, the role of ACLS1, a gene involved in the oxidation of fatty acids and key in the metabolic reprogramming of the most aggressive tumors, is being evaluated. ACSL1 is specifically expressed in one of the metabolic groups described in Objective 1. This group is clinically defined by hyperdiploidy and poor prognosis.

Objective 3. In vitro and in vivo validation of selected targets and response biomarkers. We are currently conducting in-vitro validation of the targets discussed above and their associated response biomarkers. While the effect of UAP1 inhibition was unclear, we could elucidate that CTPS1 inhibition was lethal in different MM cell lines, using both selective inhibitors and CRISPR gene knockout experiments. Thus, CTPS1 is promising therapeutic strategy in MM.  The role of ACSL1 in under study.