Publications by authors named "Maurizio Scaltriti"

The co-occurrence of germline and somatic oncogenic alterations is frequently observed in breast cancer, but their combined biologic and clinical significance has not been evaluated. To assess the role of germline-somatic interactions on outcomes in routine practice, we developed an integrated clinicogenomic pipeline to analyze the genomes of over 4,500 patients with breast cancer. We find that germline (g) -associated tumors are enriched for loss-of-function mutations and manifest poor outcomes on standard-of-care, front-line CDK4/6 inhibitor (CDK4/6i) combinations.

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The incorporation of novel therapeutic agents such as antibody-drug conjugates, radio-conjugates, T-cell engagers, and chimeric antigen receptor cell therapies represents a paradigm shift in oncology. Cell-surface target quantification, quantitative assessment of receptor internalization, and changes in the tumor microenvironment (TME) are essential variables in the development of biomarkers for patient selection and therapeutic response. Assessing these parameters requires capabilities that transcend those of traditional biomarker approaches based on immunohistochemistry, in situ hybridization and/or sequencing assays.

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Article Synopsis
  • Researchers studied advanced cancers to find the best targeted treatments by looking at gene changes in tumors.
  • They tested samples from 304 patients and found that most (78%) had important gene changes, with many tumors showing a marker called PD-L1.
  • The findings suggest that understanding the specific gene changes in different cancer types can help doctors decide on treatments and get patients into clinical trials.
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Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2.

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Purpose: Dysregulation of the PI3K pathway is one of the most common events in breast cancer. Here we investigate the activity of the PI3K inhibitor MEN1611 at both molecular and phenotypic levels by dissecting and comparing its profile and efficacy in HER2 + breast cancer models with other PI3K inhibitors.

Methods: Models with different genetic backgrounds were used to investigate the pharmacological profile of MEN1611 against other PI3K inhibitors.

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Purpose: To comprehensively characterize tissue-specific and molecular subclasses of multiple PIK3CA (multi-PIK3CA) mutations and assess their impact on potential therapeutic outcomes.

Experimental Design: We profiled a pan-cancer cohort comprised of 352,392 samples across 66 tumor types using a targeted hybrid capture-based next-generation sequencing panel covering at least 324 cancer-related genes. Molecularly defined subgroups, allelic configuration, clonality, and mutational signatures were identified and tested for association with PI3K inhibitor therapeutic response.

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CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89).

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We aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.

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Unlabelled: The phosphoinositide 3-kinase (PI3K) pathway regulates proliferation, survival, and metabolism and is frequently activated across human cancers. A comprehensive elucidation of how this signaling pathway controls transcriptional and cotranscriptional processes could provide new insights into the key functions of PI3K signaling in cancer. Here, we undertook a transcriptomic approach to investigate genome-wide gene expression and transcription factor activity changes, as well as splicing and isoform usage dynamics, downstream of PI3K.

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Article Synopsis
  • The study confirms that the RET inhibitor selpercatinib is effective in treating RET-driven cancers but explores why some patients respond poorly or develop resistance.
  • Pre-treatment genetic factors generally do not influence how patients respond to selpercatinib, except for rare cases linked to RAS mutations.
  • Resistance to selpercatinib typically arises through MAPK pathway reactivation, involving either mutations related to RET or the selection of RET-wildtype tumor cells, suggesting that combination therapies may be necessary for ongoing treatment.
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Background: Although the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Therefore, we aimed to characterize the effect of MEK1/2 inhibition on the tumor microenvironment (TME) of MAPK-driven HNC, elucidate tumor-host interaction mechanisms facilitating immune escape on treatment, and apply rationale-based therapy combination immunotherapy and MEK1/2 inhibitor to induce tumor clearance.

Methods: Mouse syngeneic tumors and xenografts experiments were used to analyze tumor growth in vivo.

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Phosphoinositide-3- kinase (PI3K) signaling regulates cellular proliferation, survival and metabolism, and its aberrant activation is one of the most frequent oncogenic events across human cancers. In the last few decades, research focused on the development of PI3K inhibitors, from preclinical tool compounds to the highly specific medicines approved to treat patients with cancer. Herein we discuss current paradigms for PI3K inhibitors in cancer therapy, focusing on clinical data and mechanisms of action.

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Pancreatic neoplasms are heterogenous and have traditionally been classified by assessing their lines of cellular differentiation using histopathologic methods, particularly morphologic and immunohistochemical evaluation. These methods frequently identify overlapping differentiation along ductal, acinar, and neuroendocrine lines, raising diagnostic challenges as well as questions regarding the relationship of these neoplasms. Neoplasms with acinar differentiation, in particular, frequently show more than one line of differentiation based on immunolabeling.

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Progress in the field of precision medicine has changed the landscape of cancer therapy. Precision medicine is propelled by technologies that enable molecular profiling, genomic analysis, and optimized drug design to tailor treatments for individual patients. Although precision medicines have resulted in some clinical successes, the use of many potential therapeutics has been hindered by pharmacological issues, including toxicities and drug resistance.

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Background: The SOLTI-1301 AGATA study aimed to assess the feasibility of a multi-institutional molecular screening program to better characterize the genomic landscape of advanced breast cancer (ABC) and to facilitate patient access to matched-targeted therapies in Spain.

Methods: DNA sequencing of 74 cancer-related genes was performed using FFPE tumor samples in three different laboratories with three different gene panels. A multidisciplinary advisory board prospectively recommended potential targeted treatments.

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Purpose: amplification (amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multi-tyrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for amp breast cancer. High-level amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively.

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To find metastatic recurrence biomarkers of triple-negative breast cancer (TNBC) treated by neoadjuvant chemotherapy and anti-EGFR antibodies (NAT), we evaluated tumor genomic, transcriptomic, and immune features, using MSK-IMPACT assay, gene arrays, Nanostring technology, and TIL assessment on H&E. Six patients experienced a rapid fatal recurrence (RR) and other 6 had later non-fatal recurrences (LR). Before NAT, RR had low expression of 6 MHC class I and 13 MHC class II genes but were enriched in upregulated genes involved in the cell cycle-related pathways.

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Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer.

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Article Synopsis
  • * Research shows that UGP2 is vital for the growth and maintenance of PDAC, as its expression is regulated by the YAP-TEAD transcription factor complex.
  • * Reducing UGP2 levels results in lower glycogen and affects important protein modifications needed for cancer cell survival, highlighting its potential as a therapeutic target for difficult-to-treat PDACs.
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Article Synopsis
  • A network-based mathematical model was used to identify how estrogen receptor positive (ER) -mutant breast cancer responds to the PI3Kα inhibitor alpelisib and potential drug combinations.
  • The study found that combining alpelisib with BH3 mimetics, like MCL1 inhibitors, enhanced treatment effectiveness, and revealed FOXO3 downregulation as a new resistance mechanism.
  • New cell line-specific models accurately predicted how different cancer cells responded to drug combinations, showcasing the potential of mathematical models to tackle cancer drug resistance issues.
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