Graziana Digiacomo's research while affiliated with Università di Parma and other places

Publications (24)

Article
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Background: The loss of the CDKN2A/ARF (cyclin-dependent kinase inhibitor 2A/alternative reading frame) gene is the most common alteration in malignant pleural mesothelioma (MPM), with an incidence of about 70%, thus representing a novel target for mesothelioma treatment. In the present study, we evaluated the antitumor potential of combining the s...
Article
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Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with rising incidence and poor prognosis. The lack of reliable prognostic biomarkers hampers the individual evaluation of the survival and recurrence potential. Methods: Here, we investigate the value of plasma levels of two potential key players in molecular mechan...
Article
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Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest solid tumors and is estimated to become a leading cause of cancer-related death in coming years. Despite advances in surgical approaches and the emergence of new chemotherapy options, its poor prognosis has not improved in the last decades. The current treatment for PDAC is the combina...
Article
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Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) o...
Article
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Advanced hepatocarcinoma (HCC) is an aggressive malignancy with poor prognosis and limited treatment options. Alterations of the cyclin D-CDK4/6-Rb pathway occur frequently in HCC, providing the rationale for its targeting at least in a molecular subset of HCC. In a panel of HCC cell lines, we investigated whether the CDK4/6 inhibitor palbociclib m...
Article
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Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6...
Article
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Immunotherapy has significantly changed the treatment landscape for advanced non-small-cell lung cancer (NSCLC) with the introduction of drugs targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1). In particular, the addition of the anti-PD-1 antibody pembrolizumab to platinum-pemetrexed chemotherapy resulted i...
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Background The third generation Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) osimertinib has been initially approved for T790M positive Non-Small Cell Lung Cancer (NSCLC) and more recently for first-line treatment of EGFR-mutant T790M negative NSCLC patients. Similarly to previous generation TKIs, despite the high respons...
Article
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Triple Negative Breast Cancer (TNBC) is a challenging disease due to the lack of druggable targets; therefore, chemotherapy remains the standard of care and the identification of new targets is a high clinical priority. Alterations in the components of the cell cycle machinery have been frequently reported in cancer; given the success obtained with...
Article
Background Osimertinib is a new third-generation, epidermal growth factor receptor-tyrosine kinase inhibitor highly selective for the epidermal growth factor receptor with both activating and T790M mutations. A recent phase III trial showed a statistically significant progression-free survival benefit with osimertinib vs. gefitinib or erlotinib as...
Article
Second- and third-generation inhibitors of EGFR possess an acrylamide group which alkylates Cys797, allowing to overcome resistance due to insurgence of T790M mutation. Less reactive warheads, yet capable to bind the target cysteine, may be useful to design newer and safer inhibitors. In the present work, we synthesized a 2-chloro-N-(4-(phenylamino...
Article
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Background: Cell cycle regulators have gain attention as potential targets for anticancer therapy. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which coordinate the G1-S transition. Palbociclib is currently approved for the treatment of hormone receptor positive, HER2-negative advanced breast cancer (BC) in...
Article
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Background Osimertinib is a third-generation EGFR-TKI with a high selective potency against T790M-mutant NSCLC patients. Considering that osimertinib can lead to enhanced HER-2 expression on cell surface and HER-2 overexpression is a mechanism of resistance to osimertinib, this study was addressed to investigate the potential of combining osimertin...
Article
Full-text available
Malignant pleural mesothelioma (MPM) is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF, encoding for the cell cycle inhibitors p16INK4a and p14ARF, deleted in about 70% of MPM cases. Considering the high frequency of alterations of this gene, we test...
Article
Full-text available
Fibroblast Growth Factor Receptor (FGFR) signaling is a complex pathway which controls several processes, including cell proliferation, survival, migration, and metabolism. FGFR1 signaling is frequently deregulated via amplification/over-expression in NSCLC of squamous histotype (SQCLC), however its inhibition has not been successfully translated i...
Article
Full-text available
Squamous cell lung carcinoma (SCC) accounts for 30% of patients with NSCLC and to date, no molecular targeted agents are approved for this type of tumor. However, recent studies have revealed several oncogenic mutations in SCC patients, including an alteration of the PI3K/AKT pathway, i.e. PI3K point mutations and amplification, AKT mutations and l...

Citations

... This requires immunotherapy and TGF-beta inhibitors to achieve a greater therapeutic response [178,179]. Cancers including lung, colon and breast cancer are more resistant to treatment than other types of cancer [180][181][182]. That is because tumor cells can influence TIME by engaging immune cells that prefer an immunosuppressive response. ...
... Radical surgery is the only potentially curative treatment, though, even in the group of radically resected patients, the five-year survival rate is below 25% [3]. There are several reasons for the dismal prognosis of PDAC: the retroperitoneal location with late onset of symptoms, the biological aggressiveness characterized by early metastasis-around 50% of patients have metastatic disease at presentation [4,5], and the impressive resistance to many anticancer agents [6][7][8][9]. ...
... As shown in Figure 2, the treatment with abemaciclib, alone or combined with chemotherapy, reduced CDK6 phosphorylation at Y24 in all cell lines analyzed. Considering that Y24-phosphorylation is inhibitory, this is a peculiar result, emerged also in other cell models [22,23]. Nevertheless, abemaciclib treatment resulted in the inhibition of CDK4/6-cyclin D complex activity. ...
... These successful findings open a new possibility of treatment for MPM patients. However, CDK4/6 inhibitors, currently approved for the treatment of estrogen receptorpositive breast cancer, displayed mainly a cytostatic effect when administered alone, whereas combination therapies demonstrated an enhanced efficacy in different tumor types [26,27]. ...
... In our previous studies, we demonstrated the efficacy of the treatment with the CDK4/6 inhibitor palbociclib alone or in combination with PI3K (Phosphoinositide 3-kinases) inhibitors in a panel of MPM cell lines [8,9], and recently these findings have been corroborated by other studies [10]. More importantly, the phase 2 clinical trial Mist2 showed encouraging results in MPM tumors, demonstrating the clinical activity of abemaciclib treatment in these patients [11]. ...
... Thus, inducing increased PD-L1 expression in tumor tissues; therefore, the combination of anti-PD-1 mAbs further enhances the efficacy of the antitumor therapy [24]. Moreover, a previous study has revealed that pemetrexed induces elevated PD-L1 expression on A549 cells via activation of the STAT3 pathway [25]. In our study, a higher PD-L1 expression was also observed in the P0 + C3 group. ...
... However, the timing, the drug concentration and the sequence of drug exposure might play a critical role in drug activity, as recently demonstrated in different tumor types. In particular, the sequential combination of CDK4/6 inhibitors and paclitaxel-based chemotherapy produced antiproliferative and pro-apoptotic effects in TNBC (triple-negative breast cancer) cell lines associated with an impairment of glucose metabolism [30], and recently, the efficacy of the simultaneous combination of gemcitabine/cisplatin-based chemotherapy and CDK4/6 inhibitors has been demonstrated also in biliary tract cancers [31]. ...
... In our study, we observed that Fasudil had stronger inhibitory effect in gefitinib-resistant H1975 cells than that in gefitinib-sensitive cells. Some researches inferred that such resistance mechanisms of osimertinib were similar to those of other firstor second-generation TKIs [46]. Therefore, to enhance the clinical significance of Fasudil here and now, it is worth further studying the synergistic effect of Fasudil and osimertinib, especially in osimertinib-resistant situations. ...
... Non-small cell lung cancer (NSCLC) is the major histological subtype of lung cancer. Approximately 50% of Asian and 10% Caucasian NSCLC patients have tumors consisting of at least one epidermal growth factor receptor (EGFR)-activating mutation [1]. Prior to the discovery of EGFR-tyrosine kinase inhibitors (EGFR-TKIs), NSCLC patients with EGFR mutations were treated with conventional chemotherapy and had poor treatment outcomes [2]. ...
... There has been a persistent search to identify new, potent and selective EGFR inhibitors which would be effective also towards the mutant strains. The surge to identify such therapeutic entities has been chemically diverse, ranging from quianazolinones [10,11], thienopyrimidines [12,13], 4-aminoquinazolines [14,15] pyrazolopyrimidines [16], pyrrolopyrimidine [17], substituted pyridines [18], substituted pyrimidines [18], biquinoline-pyridines [19], 6-oxooxazolidine-quinazolines [20], pyridopyrimidine [21], oxazoloquinazolinone [22], phthalazines [23], oxadiazoles [24]. This gave us an impetus to explore the chemical space further and search for novel EGFR inhibitors, which can potentially be a starting point for further exploration to make them highly selective and active against mutant strains. ...