RESUMO
C-X-C motif chemokine receptor 4 (CXCR4) is an attractive target for cancer diagnosis and treatment, as it is overexpressed in many solid and hematologic malignancies. This study investigated the feasibility of CXCR4-directed imaging with PET/CT using 68Ga-pentixafor to visualize and quantify disease involvement in myeloproliferative neoplasms (MPNs). Methods: Twelve patients with MPNs (4 with primary myelofibrosis, 6 with essential thrombocythemia, and 2 with polycythemia vera) and 5 controls underwent 68Ga-pentixafor PET/CT. Imaging findings were compared with immunohistochemical stainings, laboratory data, and splenic volume. Results:68Ga-pentixafor PET/CT was visually positive in 12 of 12 patients, and CXCR4 target specificity could be confirmed by immunohistochemical staining. A significantly higher tracer uptake could be detected in the bone marrow of MPN patients (SUVmean, 6.45 ± 2.34 vs. 4.44 ± 1.24). Dynamic changes in CXCR4 expression determined by 68Ga-pentixafor PET/CT corresponded with treatment response. Conclusion:68Ga-pentixafor PET/CT represents a novel diagnostic tool to noninvasively detect and quantify the extent of disease involvement in MPNs.
Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
Cereblon is the direct binding target of the immunomodulatory drugs (IMiDs) that are commonly used to treat multiple myeloma (MM), the second most frequent hematologic malignancy. Patients respond well to initial treatment with IMiDs, but virtually all patients develop drug resistance over time, and the underlying mechanisms are poorly understood. We identified an as yet undescribed DNA hypermethylation in an active intronic CRBN enhancer. Differential hypermethylation in this region was found to be increased in healthy plasma cells, but was more pronounced in IMiD-refractory MM. Methylation significantly correlated with decreased CRBN expression levels. DNA methyltransferase inhibitor (DNTMi) in vitro experiments induced CRBN enhancer demethylation, and sensitizing effects on lenalidomide treatment were observed in 2 MM cell lines. Thus, we provide first evidence that aberrant CRBN DNA methylation is a novel mechanism of IMiD resistance in MM and may predict IMiD response prior to treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antineoplásicos Imunológicos/uso terapêutico , Agentes de Imunomodulação/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Ubiquitina-Proteína Ligases/genética , Metilação de DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Elementos Facilitadores Genéticos/efeitos dos fármacos , Humanos , Íntrons/efeitos dos fármacos , Mieloma Múltiplo/genéticaRESUMO
Constitutive phosphatidylinositide 3-kinase (PI3K) signalling has been implicated in multiple myeloma (MM) pathophysiology and is regarded as an actionable target for pharmacological intervention. Isoform-specific PI3K inhibition may offer the most focused treatment approach and could result in greater clinical efficacy and reduced side effects. We therefore performed isoform-specific knockdown of PIK3CA, PIK3CB, PIK3CD, and PIK3CG to analyse their individual contributions to MM cell survival and downstream signalling. In addition, we tested the effectivity of the novel PI3K isoform-specific inhibitors BYL-719 (PIK3CA), TGX-221 (PIK3CB), CAL-101 (PIK3CD), and CAY10505 (PIK3CG). We found the PIK3CA isoform to be of paramount importance for constitutive Akt activity in MM cells, and - in contrast to inhibition of other class I isoforms - only the blockade of PIK3CA was sufficient to induce cell death in a sizeable subgroup of MM samples. Furthermore, pharmacological PIK3CA inhibition in combination treatments of BYL-719 and established anti-myeloma agents resulted in strongly enhanced MM cell death. Our data thus clearly indicate therapeutic potential of PIK3CA inhibitors and support their clinical evaluation in multiple myeloma.