Evaluation of tissue- and plasma-derived tumor mutational burden (TMB) and genomic alterations of interest in CheckMate 848, a study of nivolumab combined with ipilimumab and nivolumab alone in patients with advanced or metastatic solid tumors with high TMB.

Background: An accumulation of somatic mutations in tumors leads to increased neoantigen levels and antitumor immune response. Tumor mutational burden (TMB) reflects the rate of somatic mutations in the tumor genome, as determined from tumor tissue (tTMB) or blood (bTMB). While high tTMB is a biomarker of immune checkpoint inhibitor (ICI) treatment efficacy, few studies have explored the clinical utility of bTMB, a less invasive alternative for TMB assessment.

Addressing resistance to PD-1/PD-(L)1 pathway inhibition: considerations for combinatorial clinical trial designs.

With multiple PD-(L)1 inhibitors approved across dozens of indications by the US Food and Drug Administration, the number of patients exposed to these agents in adjuvant, first-line metastatic, second-line metastatic, and refractory treatment settings is increasing rapidly. Although some patients will experience durable benefit, many have either no clinical response or see their disease progress following an initial response to therapy. There is a significant need to identify therapeutic approaches to overcome resistance and confer clinical benefits for these patients.

Camptothecin induces nuclear export of prohibitin preferentially in transformed cells through a CRM-1-dependent mechanism.

Prohibitin is a growth-suppressive protein that has multiple functions in the nucleus and the mitochondria. Our earlier studies had shown that prohibitin represses the activity of E2F transcription factors while enhancing p53-mediated transcription. At the same time, prohibitin has been implicated in mediating the proper folding of mitochondrial proteins.

Disruption of the Rb--Raf-1 interaction inhibits tumor growth and angiogenesis.

The retinoblastoma tumor suppressor protein (Rb) plays a vital role in regulating mammalian cell cycle progression and inactivation of Rb is necessary for entry into S phase. Rb is inactivated by phosphorylation upon growth factor stimulation of quiescent cells, facilitating the transition from G(1) phase to S phase. Although the signaling events after growth factor stimulation have been well characterized, it is not yet clear how these signals contact the cell cycle machinery.

Prohibitin induces the transcriptional activity of p53 and is exported from the nucleus upon apoptotic signaling.

Prohibitin, a potential tumor suppressor protein, has been shown to inhibit cell proliferation and repress E2F transcriptional activity. Though prohibitin has potent transcriptional functions in the nucleus, a mitochondrial role for prohibitin has also been proposed. Here we show that prohibitin is predominantly nuclear in two breast cancer cell lines where it co-localizes with E2F1 and p53.

Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression.

The potential tumor suppressor protein prohibitin can prevent cell proliferation and this required its binding to the Rb protein. Prohibitin could repress the transcriptional activity of E2F family members and this required a part of the marked box region of E2F. The sub-cellular localization of prohibitin has been variously attributed to the mitochondria as well as the inner cell membrane.

Differential regulation of Rb family proteins and prohibitin during camptothecin-induced apoptosis.

Prohibitin, a potential tumor suppressor, is known to induce growth suppression and repress E2F-mediated transcription. These growth regulatory functions of prohibitin require a physical interaction with the Rb protein. We now find that prohibitin protects cells from apoptosis mediated by camptothecin, a topoisomerase I inhibitor.