Review

Authors: Marie Will, Jackson Liang, Ciara Metcalfe...

The hormone receptor oestrogen receptor-α (ER) orchestrates physiological mammary gland development, breast carcinogenesis and the progression of breast tumours into lethal, treatment-refractory systemic disease. Selective antagonism of ER signalling has been one of the most successful therapeutic approaches in oncology, benefiting patients as both a cancer preventative measure and a cancer treatment strategy. However, resistance to anti-oestrogen therapy is a major clinical challenge. Over the past decade, we have gained an understanding of how breast cancers evolve under the pressure of anti-oestrogen therapy. This is best depicted by the case of oestrogen-independent mutations in the gene encoding ER (ESR1), which are virtually absent in primary breast cancer but highly prevalent (20-40%) in anti-oestrogen-treated metastatic disease. These and other findings highlight the 'evolvability' of ER breast cancer and the need to understand molecular processes by which this evolution occurs. Recent development and approval of next-generation ER antagonists to target ESR1-mutant breast cancer underscores the clinical importance of this evolvability and sets a new paradigm for the treatment of ER breast cancers.

Topics: Humans; Female; Breast Neoplasms; Drug Resistance, Neoplasm; Estrogens; Signal Transduction

PubMed: 37500767
DOI: 10.1038/s41568-023-00604-3

Authors: Yoann Pradat, Julien Viot, Andrey A Yurchenko...

UNLABELLED

Metastatic relapse after treatment is the leading cause of cancer mortality, and known resistance mechanisms are missing for most treatments administered to patients. To bridge this gap, we analyze a pan-cancer cohort (META-PRISM) of 1,031 refractory metastatic tumors profiled via whole-exome and transcriptome sequencing. META-PRISM tumors, particularly prostate, bladder, and pancreatic types, displayed the most transformed genomes compared with primary untreated tumors. Standard-of-care resistance biomarkers were identified only in lung and colon cancers-9.6% of META-PRISM tumors, indicating that too few resistance mechanisms have received clinical validation. In contrast, we verified the enrichment of multiple investigational and hypothetical resistance mechanisms in treated compared with nontreated patients, thereby confirming their putative role in treatment resistance. Additionally, we demonstrated that molecular markers improve 6-month survival prediction, particularly in patients with advanced breast cancer. Our analysis establishes the utility of the META-PRISM cohort for investigating resistance mechanisms and performing predictive analyses in cancer.

SIGNIFICANCE

This study highlights the paucity of standard-of-care markers that explain treatment resistance and the promise of investigational and hypothetical markers awaiting further validation. It also demonstrates the utility of molecular profiling in advanced-stage cancers, particularly breast cancer, to improve the survival prediction and assess eligibility to phase I clinical trials. This article is highlighted in the In This Issue feature, p. 1027.

Topics: Male; Humans; Transcriptome; Neoplasm Recurrence, Local; Breast Neoplasms; Genomics; Gene Expression Profiling; Neoplasms, Second Primary

PubMed: 36862804
DOI: 10.1158/2159-8290.CD-22-0966

Authors: Shrabanti Chowdhury, Jacob J Kennedy, Richard G Ivey...

To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.

Topics: Female; Humans; Cystadenocarcinoma, Serous; Ovarian Neoplasms; Proteogenomics

PubMed: 37541199
DOI: 10.1016/j.cell.2023.07.004

Review

Authors: Qian Zhou, Yu Meng, Daishi Li...

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation of iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in the biological processes of tumors. Intriguingly, mesenchymal and dedifferentiated cancer cells, which are usually resistant to apoptosis and traditional therapies, are exquisitely vulnerable to ferroptosis, further underscoring its potential as a treatment approach for cancers, especially for refractory cancers. However, the impact of ferroptosis on cancer extends beyond its direct cytotoxic effect on tumor cells. Ferroptosis induction not only inhibits cancer but also promotes cancer development due to its potential negative impact on anticancer immunity. Thus, a comprehensive understanding of the role of ferroptosis in cancer is crucial for the successful translation of ferroptosis therapy from the laboratory to clinical applications. In this review, we provide an overview of the recent advancements in understanding ferroptosis in cancer, covering molecular mechanisms, biological functions, regulatory pathways, and interactions with the tumor microenvironment. We also summarize the potential applications of ferroptosis induction in immunotherapy, radiotherapy, and systemic therapy, as well as ferroptosis inhibition for cancer treatment in various conditions. We finally discuss ferroptosis markers, the current challenges and future directions of ferroptosis in the treatment of cancer.

Topics: Humans; Ferroptosis; Neoplasms; Immunotherapy; Apoptosis; Iron; Tumor Microenvironment

PubMed: 38453898
DOI: 10.1038/s41392-024-01769-5

Review

Authors: Anna C Lilly, Igor Astsaturov, Erica A Golemis...

Pancreatic cancer is typically detected at an advanced stage, and is refractory to most forms of treatment, contributing to poor survival outcomes. The incidence of pancreatic cancer is gradually increasing, linked to an aging population and increasing rates of obesity and pancreatitis, which are risk factors for this cancer. Sources of risk include adipokine signaling from fat cells throughout the body, elevated levels of intrapancreatic intrapancreatic adipocytes (IPAs), inflammatory signals arising from pancreas-infiltrating immune cells and a fibrotic environment induced by recurring cycles of pancreatic obstruction and acinar cell lysis. Once cancers become established, reorganization of pancreatic tissue typically excludes IPAs from the tumor microenvironment, which instead consists of cancer cells embedded in a specialized microenvironment derived from cancer-associated fibroblasts (CAFs). While cancer cell interactions with CAFs and immune cells have been the topic of much investigation, mechanistic studies of the source and function of IPAs in the pre-cancerous niche are much less developed. Intriguingly, an extensive review of studies addressing the accumulation and activity of IPAs in the pancreas reveals that unexpectedly diverse group of factors cause replacement of acinar tissue with IPAs, particularly in the mouse models that are essential tools for research into pancreatic cancer. Genes implicated in regulation of IPA accumulation include KRAS, MYC, TGF-β, periostin, HNF1, and regulators of ductal ciliation and ER stress, among others. These findings emphasize the importance of studying pancreas-damaging factors in the pre-cancerous environment, and have significant implications for the interpretation of data from mouse models for pancreatic cancer.

Topics: Mice; Animals; Pancreatic Neoplasms; Pancreatitis; Pancreas; Acinar Cells; Carcinoma, Pancreatic Ductal; Tumor Microenvironment

PubMed: 37452870
DOI: 10.1007/s00018-023-04855-z

Review

Authors: Reetu Mukherji, Dipanjan Debnath, Marion L Hartley...

Pancreatic adenocarcinoma remains one of the most lethal cancers globally, with a significant need for improved therapeutic options. While the recent breakthroughs of immunotherapy through checkpoint inhibitors have dramatically changed treatment paradigms in other malignancies based on considerable survival benefits, this is not so for pancreatic cancer. Chemotherapies with modest benefits are still the cornerstone of advanced pancreatic cancer treatment. Pancreatic cancers are inherently immune-cold tumors and have been largely refractory to immunotherapies in clinical trials. Understanding and overcoming the current failures of immunotherapy through elucidating resistance mechanisms and developing novel therapeutic approaches are essential to harnessing the potential durable benefits of immune-modulating therapy in pancreatic cancer patients.

Topics: Humans; Pancreatic Neoplasms; Adenocarcinoma; Immunotherapy; Immunologic Factors

PubMed: 36290818
DOI: 10.3390/curroncol29100541

Review

Authors: Yurie Yamamoto, Hiroaki Kasashima, Yasuhiro Fukui...

The prognosis for patients with cancers known for a highly activated stromal reaction, including diffuse-type (scirrhous) gastric cancer, consensus molecular subtype 4 (CMS4) colorectal cancer, and pancreatic ductal adenocarcinoma, is extremely poor. To explore the resistance of conventional therapy for those refractory cancers, detailed classification and investigation of the different subsets of cancer-associated fibroblasts (CAFs) involved are needed. Recent studies with a single-cell transcriptomics strategy (single-cell RNA-seq) have demonstrated that CAF subpopulations contain different origins and marker proteins with the capacity to either promote or suppress cancer progression. Through multiple signaling pathways, CAFs can promote tumor growth, metastasis, and angiogenesis with extracellular matrix (ECM) remodeling; they can also interact with tumor-infiltrating immune cells and modulate the antitumor immunological state in the tumor microenvironment (TME). Here, we review the recent literature on the various subpopulations of CAFs to improve our understanding of the cell-cell interactions in the TME and highlight future avenues for CAF-targeted therapy.

Topics: Humans; Cancer-Associated Fibroblasts; Tumor Microenvironment; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Biomarkers

PubMed: 36197901
DOI: 10.1111/cas.15609

Review

Authors: Danfeng Chen, Jingyi Wu, Duochen Jin...

The human gut is home to a large and diverse microbial community, comprising about 1,000 bacterial species. The gut microbiota exists in a symbiotic relationship with its host, playing a decisive role in the host's nutrition, immunity and metabolism. Accumulating studies have revealed the associations between gut dysbiosis or some special bacteria and various cancers. Emerging data suggest that gut microbiota can modulate the effectiveness of cancer therapies, especially immunotherapy. Manipulating the microbial populations with therapeutic intent has become a hot topic of cancer research, and the most dramatic manipulation of gut microbiota refers to fecal microbiota transplantation (FMT) from healthy individuals to patients. FMT has demonstrated remarkable clinical efficacy against Clostridium difficile infection (CDI) and it is highly recommended for the treatment of recurrent or refractory CDI. Lately, interest is growing in the therapeutic potential of FMT for other diseases, including cancers. We briefly reviewed the current researches about gut microbiota and its link to cancer, and then summarized the recent preclinical and clinical evidence to indicate the potential of FMT in cancer management as well as cancer-treatment associated complications. We also presented the rationale of FMT for cancer management such as reconstruction of intestinal microbiota, amelioration of bile acid metabolism, and modulation of immunotherapy efficacy. This article would help to better understand this new therapeutic approach for cancer patients by targeting gut microbiota.

Topics: Clostridioides difficile; Clostridium Infections; Dysbiosis; Fecal Microbiota Transplantation; Feces; Gastrointestinal Microbiome; Humans; Microbiota; Neoplasms; Treatment Outcome

PubMed: 30458058
DOI: 10.1002/ijc.32003

Review

Authors: A Kanani, T Veen, K Søreide...

BACKGROUND

Colorectal cancer (CRC) is the second most common solid organ cancer. Traditional treatment is with surgery and chemotherapy. Immunotherapy has recently emerged as a neoadjuvant therapy that could change treatment strategy in both primary resectable and metastatic CRC.

METHODS

A literature review of PubMed with a focus on studies exploring upfront immunotherapy in operable CRC, either for primary resectable stage I-III cancers or for (potentially) operable liver metastasis.

RESULTS

Immune checkpoint blockade by the programmed cell death 1 (PD-1) receptor inhibitors nivolumab and pembrolizumab and the cytotoxic T cell-associated protein 4 (CTLA-4) inhibitor ipilimumab has shown good results in both early-stage and advanced CRC. The effects of immune checkpoint inhibitors have so far been demonstrated in small phase I/II studies and predominantly in treatment-refractory stage IV disease with defect Mismatch repair (dMMR). However, recent data from phase I/II (NICHE-1) studies suggest an upfront role for immunotherapy in operable stage I-III disease. By blocking crucial immune checkpoints, cytotoxic T cells are activated and release cytotoxic signals that initiate cancer cell destruction. The very high complete response rate in dMMR operable CRC with neoadjuvant immunotherapy with nivolumab and ipilimumab, and even partial pathological response in some patients with proficient MMR (pMMR) CRC, calls for further attention to patient selection for neoadjuvant treatment, beyond MMR status alone.

CONCLUSION

Early data on the effect of immunotherapy in CRC provide new strategic thinking of treatment options in CRC for both early-stage and advanced disease, with prospects for new trials.

Topics: Antineoplastic Agents, Immunological; Colonic Neoplasms; Humans; Neoadjuvant Therapy; Rectal Neoplasms

PubMed: 34694371
DOI: 10.1093/bjs/znab342

Review

Authors: Masuko Katoh, Masaru Katoh

NOTCH1, NOTCH2, NOTCH3 and NOTCH4 are transmembrane receptors that transduce juxtacrine signals of the delta‑like canonical Notch ligand (DLL)1, DLL3, DLL4, jagged canonical Notch ligand (JAG)1 and JAG2. Canonical Notch signaling activates the transcription of BMI1 proto‑oncogene polycomb ring finger, cyclin D1, CD44, cyclin dependent kinase inhibitor 1A, hes family bHLH transcription factor 1, hes related family bHLH transcription factor with YRPW motif 1, MYC, NOTCH3, RE1 silencing transcription factor and transcription factor 7 in a cellular context‑dependent manner, while non‑canonical Notch signaling activates NF‑κB and Rac family small GTPase 1. Notch signaling is aberrantly activated in breast cancer, non‑small‑cell lung cancer and hematological malignancies, such as T‑cell acute lymphoblastic leukemia and diffuse large B‑cell lymphoma. However, Notch signaling is inactivated in small‑cell lung cancer and squamous cell carcinomas. Loss‑of‑function NOTCH1 mutations are early events during esophageal tumorigenesis, whereas gain‑of‑function NOTCH1 mutations are late events during T‑cell leukemogenesis and B‑cell lymphomagenesis. Notch signaling cascades crosstalk with fibroblast growth factor and WNT signaling cascades in the tumor microenvironment to maintain cancer stem cells and remodel the tumor microenvironment. The Notch signaling network exerts oncogenic and tumor‑suppressive effects in a cancer stage‑ or (sub)type‑dependent manner. Small‑molecule γ‑secretase inhibitors (AL101, MRK‑560, nirogacestat and others) and antibody‑based biologics targeting Notch ligands or receptors [ABT‑165, AMG 119, rovalpituzumab tesirine (Rova‑T) and others] have been developed as investigational drugs. The DLL3‑targeting antibody‑drug conjugate (ADC) Rova‑T, and DLL3‑targeting chimeric antigen receptor‑modified T cells (CAR‑Ts), AMG 119, are promising anti‑cancer therapeutics, as are other ADCs or CAR‑Ts targeting tumor necrosis factor receptor superfamily member 17, CD19, CD22, CD30, CD79B, CD205, Claudin 18.2, fibroblast growth factor receptor (FGFR)2, FGFR3, receptor‑type tyrosine‑protein kinase FLT3, HER2, hepatocyte growth factor receptor, NECTIN4, inactive tyrosine‑protein kinase 7, inactive tyrosine‑protein kinase transmembrane receptor ROR1 and tumor‑associated calcium signal transducer 2. ADCs and CAR‑Ts could alter the therapeutic framework for refractory cancers, especially diffuse‑type gastric cancer, ovarian cancer and pancreatic cancer with peritoneal dissemination. Phase III clinical trials of Rova‑T for patients with small‑cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch‑related knowledge‑base and optimize Notch‑targeted therapy for patients with cancer.

Topics: Animals; Antineoplastic Agents; Drug Development; Humans; Molecular Targeted Therapy; Neoplasms; Precision Medicine; Receptors, Notch; Signal Transduction; Tumor Microenvironment

PubMed: 31894255
DOI: 10.3892/ijmm.2019.4418