Frontiers of molecular biology of cancer

Cancer is rooted in genetic background, with the expression of oncogenesis playing a pivotal role in the early stages of tumor formation. Acquired mutations in somatic cells primarily contribute to the development of most common cancers, while specific germline mutations are responsible for rare hereditary cancer syndromes. Within the realm of cancer-associated genes, oncogenes undergo activation, exhibiting phenotypic dominance, whereas tumor suppressor genes experience inactivation, displaying phenotypic recessiveness. The ongoing effort to improve our knowledge about molecular mechanisms involves defining pathways influencing cancer therapy. Technological advancements have made it possible to identify genes integral to cancer development and have significantly contributed to the growing success of precision medicine in oncology, with targeted therapies directed against tumors and components of the tumor microenvironment. This Special Issue, titled “Molecular Biology of Cancer—Implications for Diagnosis and Treatment”, comprises a total of eight contributions. These include five original articles and three reviews, offering fresh insights into cancer biology, molecular genetics, and innovative therapeutic approaches

Prostate cancer - what about oligometastatic disease and stereotactic ablative radiotherapy? - a narrative review

Background and Objective: Oligometastatic prostate cancer (OMPC) encompasses a heterogenous group of clinical entities defined by the timing of the development of metastases. These include de novo oligometastatic, oligorecurrent and oligoprogressive prostate cancer (PrCa). We describe the evidence supporting the use of stereotactic ablative radiotherapy (SABR) to the oligometastases to improve patient outcomes in each of these settings. Methods: Published clinical trials relevant to ‘OMPC’ and ‘SABR’ where used for this narrative review. Key Content and Findings: The driving force behind this narrative review is the constantly evolving field of OMPC with an increasing number of salvage radiotherapy options changing the current treatment paradigm. We now have evidence to support that disease control can be optimised with SABR as shown in several practice changing trials including ‘ORIOLE’, ‘STOMP’ for PrCa and ‘SABR-COMET’ showing a survival advantage with a tumour agnostic salvage approach. We also describe the challenges with data interpretation and cost implications. Challenges include the small sample size for most reported trials, in combination with a lack of cost-efficiency analysis. Conclusions: SABR is a promising treatment approach for OMPC with a proven clinical benefit in some clinical settings and its use will expand in the future

Precision medicine based in epigenomics: the paradigm of carcinoma of unknown primary

Epigenetic alterations are a common hallmark of human cancer. Single epigenetic markers are starting to be incorporated into clinical practice; however, the translational use of these biomarkers has not been validated at the 'omics' level. The identification of the tissue of origin in patients with cancer of unknown primary (CUP) is an example of how epigenomics can be incorporated in clinical settings, addressing an unmet need in the diagnostic and clinical management of these patients. Despite the great diagnostic advances made in the past decade, the use of traditional diagnostic procedures only enables the tissue of origin to be determined in ∼30% of patients with CUP. Thus, development of molecularly guided diagnostic strategies has emerged to complement traditional procedures, thereby improving the clinical management of patients with CUP. In this Review, we present the latest data on strategies using epigenetics and other molecular biomarkers to guide therapeutic decisions involving patients with CUP, and we highlight areas warranting further research to engage the medical community in this unmet need

Stage 3 N2 lung cancer: A multidisciplinary therapeutic conundrum

The treatment of stage III N2 non-small cell lung cancer (NSCLC) remains debated. There is an absence of a universally agreed definition of resectability for this heterogeneous group and a lack of trial data. We reviewed and compared current international guidelines and evidence surrounding management of stage III N2 NSCLC. The Irish and Australian guidelines advise subcategorising N2 disease into N2a (may be resectable) and N2b (never resectable). On the contrary, American and British guidelines avoid subcategorising N2 disease, emphasising importance of local MDT decisions. It is suggested that evidence for resection of stage III tumours is relatively weak, but that stage IIIA should generally be considered for resection, and stage IIIB is not recommended for resection. For resectable disease, surgery may be combined with neoadjuvant chemoimmunotherapy, or adjuvant chemotherapy followed by immunotherapy and radiotherapy in selected patients. There is some evidence that technically resectable disease can be treated solely with radiotherapy with similar outcomes to resection. In the event of unresectable disease, chemoradiotherapy has been the traditional management option. However, recent studies with chemoradiotherapy alongside immunotherapy appear promising. There are many factors that influence the treatment pathway offered to patients with stage III N2 NSCLC, including patient factors, team expertise, and local resources. Therefore, the role of MDTs in defining resectability and formulating an individualised treatment plan is crucial. [Abstract copyright: © 2024. Crown.

Combining PARP Inhibition with Platinum, Ruthenium or Gold Complexes for Cancer Therapy

Platinum drugs are heavily used first-line chemotherapeutic agents for many solid tumours and have stimulated substantial interest in the biological activity of DNA-binding metal complexes. These complexes generate DNA lesions which trigger the activation of DNA damage response (DDR) pathways that are essential to maintain genomic integrity. Cancer cells exploit this intrinsic DNA repair network to counteract many types of chemotherapies. Now, advances in the molecular biology of cancer has paved the way for the combination of DDR inhibitors such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) and agents that induce high levels of DNA replication stress or single-strand break damage for synergistic cancer cell killing. In this review, we summarise early-stage, preclinical and clinical findings exploring platinum and emerging ruthenium anti-cancer complexes alongside PARPi in combination therapy for cancer and also describe emerging work on the ability of ruthenium and gold complexes to directly inhibit PARP activity

Optimized low-dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment.

The current standard of care for colorectal cancer (CRC) is a combination of chemotherapeutics, often supplemented with targeted biological drugs. An urgent need exists for improved drug efficacy and minimized side effects, especially at late-stage disease. We employed the phenotypically driven therapeutically guided multidrug optimization (TGMO) technology to identify optimized drug combinations (ODCs) in CRC. We identified low-dose synergistic and selective ODCs for a panel of six human CRC cell lines also active in heterotypic 3D co-culture models. Transcriptome sequencing and phosphoproteome analyses showed that the mechanisms of action of these ODCs converged toward MAP kinase signaling and cell cycle inhibition. Two cell-specific ODCs were translated to in vivo mouse models. The ODCs reduced tumor growth by ~80%, outperforming standard chemotherapy (FOLFOX). No toxicity was observed for the ODCs, while significant side effects were induced in the group treated with FOLFOX therapy. Identified ODCs demonstrated significantly enhanced bioavailability of the individual components. Finally, ODCs were also active in primary cells from CRC patient tumor tissues. Taken together, we show that the TGMO technology efficiently identifies selective and potent low-dose drug combinations, optimized regardless of tumor mutation status, outperforming conventional chemotherapy

Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells.

The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1-2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib