The evolving panorama of HER2-targeted treatments in metastatic urothelial cancer: A systematic review and future perspectives.

PURPOSE: HER2 alterations are potential candidates for targeted treatments in metastatic urothelial/bladder cancer (mUC). ERBB2 gene amplification and mutations are found in around 6% and 4% of mUC, respectively. METHODS: This is a systematic review of clinical trials evaluating HER2-targeting (amplification and mutations) in mUC. We assigned each study to one of the following strategies: HER2-targeting with single agents, anti-HER2 agents in combination with cytotoxic chemotherapy, dual HER2 blockade, HER2-targeted antibody-drug conjugates (ADCs), and other novel therapeutic approaches. RESULTS: 36 clinical trials (17 with results and 19 ongoing) were included. As for ERBB2 amplification, anti-HER2 single agents (5 studies) and combinations with chemotherapy (4 studies) failed to provide any benefit, whereas dual HER2 blockade through monoclonal antibodies proved active in one trial in pretreated patients. Two studies assessed single-agent targeting for ERBB2 mutations with negative results. Most promising data come from 2 studies with ADCs in ERBB2 amplified tumors (disitamab-vedotin and trastuzumab-duocarmazine), while 2 other studies with TDM-1 and ADCT-502 was discontinued due to toxicity. In this category, trastuzumab-deruxtecan and other ADCs are still under investigation for either ERBB2-amplified or mutated mUC. Novel approaches include ADCs with immunotherapy (1 study with results), CAR-T cells, and HER2-sensitising vaccines. CONCLUSIONS: ERBB2 amplification could become a novel target in mUC, although the magnitude of clinical benefit remains to be clarified. To this regard, novel ADCs are the most promising strategy. ERBB2 mutations are still at very early stage of clinical study.

The inverse correlation between robustness and sensitivity to autoregulation in two-component systems.

Two-component systems (TCS) are signal transduction systems in bacteria and many other organisms that relay the sensory signal to genetic components. TCS consist of two proteins: a histidine kinase and a response regulator that the histidine kinase activates. This seemingly simple machinery can generate complex regulatory dynamics that enables the level of gene expression that matches the input signal: many TCS response regulators act on their own genes as transcription factors, resulting in a positive autoregulation mechanism. This regulation, in return, modulates the transcription factor activity as a function of the input signal. Positive autoregulation does not necessarily result in positive feedback. Sensitivity to autoregulation is quantified as the output level amplification resulting from the positive autoregulation mechanism. Another structural property of these systems is formally characterized as "robustness": in a robust TCS, the output of the system is solely a function of the input signal. Thus, a robust TCS remains insensitive to fluctuations in the concentrations of its protein components and, this way, maintains the precision in the output transcription factor activity in response to input stimulus. In this paper, we show with a formal model that TCS operate on a spectrum of inverse correlation between robustness and sensitivity to autoregulation. Our model predicts that the modulation by positive autoregulation is a function of loss in TCS robustness, for example, by spontaneous dephosphorylation of the histidine kinase. Consequently, the loss in robustness provides a proportional modulation by positive autoregulation to widen the response range with a scaled amplification of the output. At the other end of the spectrum, in the presence of a strictly robust TCS machinery, amplification of the transcription factor activity by autoregulation is diminished. We show that our results are in agreement with published experimental results. Our results suggest that these TCS evolve to converge at a trade-off between robustness and positive autoregulation.

Stochastic Simulations as a Tool for Assessing Signal Fidelity in Gene Expression in Synthetic Promoter Design.

The design and development of synthetic biology applications in a workflow often involve connecting modular components. Whereas computer-aided design tools are picking up in synthetic biology as in other areas of engineering, the methods for verifying the correct functioning of living technologies are still in their infancy. Especially, fine-tuning for the right promoter strength to match the design specifications is often a lengthy and expensive experimental process. In particular, the relationship between signal fidelity and noise in synthetic promoter design can be a key parameter that can affect the healthy functioning of the engineered organism. To this end, based on our previous work on synthetic promoters for the E. coli PhoBR two-component system, we make a case for using chemical reaction network models for computational verification of various promoter designs before a lab implementation. We provide an analysis of this system with extensive stochastic simulations at a single-cell level to assess the signal fidelity and noise relationship. We then show how quasi-steady-state analysis via ordinary differential equations can be used to navigate between models with different levels of detail. We compare stochastic simulations with our full and reduced models by using various metrics for assessing noise. Our analysis suggests that strong promoters with low unbinding rates can act as control tools for filtering out intrinsic noise in the PhoBR context. Our results confirm that even simpler models can be used to determine promoters with specific signal to noise characteristics.

Liquid biopsy for rectal cancer: A systematic review.

BACKGROUND: The management of locally advanced rectal cancer (RC) is an evolving clinical field where the multidisciplinary approach can reach its best, and liquid biopsy for obtaining tumor-derived component such as circulating tumor DNA (ctDNA) might provide complementary informations. METHODS: A systematic review of studies available in literature of liquid biopsy in non-metastatic RC has been performed according to PRISMA criteria to assess the role of ctDNA as a diagnostic, predictive and prognostic biomarker in this setting. RESULTS: Twenty-five publications have been retrieved, of which 8 full-text articles, 7 abstracts and 10 clinical trials. Results have been categorized into three groups: diagnostic, predictive and prognostic. Few but promising data are available about the use of liquid biopsy for early diagnosis of RC, with the main limitation of sensitivity due to low concentrations of ctDNA in this setting. In terms of prediction of response to chemoradiation, still inconclusive data are available about the utility of a pre-treatment liquid biopsy, whereas some studies report a positive correlation with a dynamic (pre/post-treatment) monitoring. The presence of minimal residual disease by ctDNA was consistently associated with worse prognosis across studies. CONCLUSIONS: The use of liquid biopsy for monitoring response to chemoradiation and assess the risk of disease recurrence are the most advanced potential applications for liquid biopsy in RC, with implications also in the context of non-operative management strategies.