Long-term outcomes of PARP inhibitors in ovarian cancer: survival, adverse events, and post-progression insights

Poly-ADP-ribose polymerase inhibitors (PARPis) have revolutionized the management of BRCA-mutated (BRCAmut) and homologous recombination deficiency (HRD)-positive ovarian cancer (OC). While long-term analyses clearly support the use of PARPi as maintenance therapy after fi rst-line chemotherapy, recent data have raised concerns on detrimental overall survival (OS) in non-BRCAmut OC, a greater incidence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and unfavorable outcomes following subsequent platinum-based chemotherapy in pretreated OC patients. In this report we discuss the long-term follow-up results from phase III trials in pretreated OC patients, which led to the Food and Drug Administration's withdrawal of PARPi indications in this setting. We summarize the newly available evidence concerning the risk of MDS/AML and the post-progression efficacy results after PARPi. We emphasize the importance of long-term follow-up and real-world data coming from international registries to define the efficacy and safety of stopping PARPi at relapse at a pre-specified time. To this point, biomarkers able to identify the patients who will experience long-term remission with PARPi maintenance or develop early resistance are urgently needed to guide treatment decision and duration

The Role of PARP Inhibitors in the Ovarian Cancer Microenvironment: Moving Forward From Synthetic Lethality

PARP inhibitors (PARPi) have shown promising clinical results and have revolutionized the landscape of ovarian cancer management in the last few years. While the core mechanism of action of these drugs has been largely analyzed, the interaction between PARP inhibitors and the microenvironment has been scarcely researched so far. Recent data shows a variety of mechanism through which PARPi might influence the tumor microenvironment and especially the immune system response, that might even partly be the reason behind PARPi efficacy. One of many pathways that are affected is the cGAS-cGAMP-STING; the upregulation of STING (stimulator of interferon genes), produces more Interferon ϒ and pro inflammatory cytokines, thus increasing intratumoral CD4+ and CD8+ T cells. Upregulation of immune checkpoints such as PD1-PDL1 has also been observed. Another interesting mechanism of interaction between PARPi and microenvironment is the ability of PARPi to kill hypoxic cells, as these cells show an intrinsic reduction in the expression and function of the proteins involved in HR. This process has been defined “contextual synthetic lethality”. Despite ovarian cancer having always been considered a poor responder to immune therapy, data is now shedding a new light on the matter. First, OC is much more heterogenous than previously thought, therefore it is fundamental to select predictive biomarkers for target therapies. While single agent therapies have not yielded significant results on the long term, influencing the immune system and the tumor microenvironment via the concomitant use of PARPi and other target therapies might be a more successful approach

Immuno-Metabolism and Microenvironment in Cancer: Key Players for Immunotherapy

Immune checkpoint inhibitors (ICIs) have changed therapeutic algorithms in several malignancies, although intrinsic and secondary resistance is still an issue. In this context, the dysregulation of immuno-metabolism plays a leading role both in the tumor microenvironment (TME) and at the host level. In this review, we summarize the most important immune-metabolic factors and how they could be exploited therapeutically. At the cellular level, an increased concentration of extracellular adenosine as well as the depletion of tryptophan and uncontrolled activation of the PI3K/AKT pathway induces an immune-tolerant TME, reducing the response to ICIs. Moreover, aberrant angiogenesis induces a hypoxic environment by recruiting VEGF, Treg cells and immune-suppressive tumor associated macrophages (TAMs). On the other hand, factors such as gender and body mass index seem to affect the response to ICIs, while the microbiome composition (and its alterations) modulates both the response and the development of immune-related adverse events. Exploiting these complex mechanisms is the next goal in immunotherapy. The most successful strategy to date has been the combination of antiangiogenic drugs and ICIs, which prolonged the survival of patients with non-small-cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), while results from tryptophan pathway inhibition studies are inconclusive. New exciting strategies include targeting the adenosine pathway, TAMs and the microbiota with fecal microbiome transplantation

When speaker identity is unavoidable: neural processing of speaker identity cues in natural speech

Speech sound acoustic properties vary largely across speakers and accents. When perceiving speech, adult listeners normally disregard non-linguistic variation caused by speaker or accent differences, in order to comprehend the linguistic message, e.g. to correctly identify a speech sound or a word. Here we tested whether the process of normalizing speaker and accent differences, facilitating the recognition of linguistic information, is found at the level of neural processing, and whether it is modulated by the listeners’ native language. In a multi-deviant oddball paradigm, native and nonnative speakers of Dutch were exposed to naturally-produced Dutch vowels varying in speaker, sex, accent, and phoneme identity. Unexpectedly, the analysis of mismatch negativity (MMN) amplitudes elicited by each type of change shows a large degree of early perceptual sensitivity to non-linguistic cues. This finding on percep- tion of naturally-produced stimuli contrasts with previous studies examining the perception of synthetic stimuli wherein adult listeners automatically disregard acoustic cues to speaker identity. The present finding bears relevance to speech normalization theories, suggesting that at an unattended level of pro- cessing, listeners are indeed sensitive to changes in fundamental frequency in natural speech tokens.Theoretical and Experimental Linguistic