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Cancer therapy has advanced significantly in recent years, however, cancer remains a major health problem that requires further discovery and innovation to improve outcomes and quality of life for patients. Nature Cancer presents a Series of commissioned Review and Perspective articles highlighting emerging concepts in cancer therapy, novel therapeutic approaches and the challenges in translating preclinical findings into clinical benefit, accompanied by a collection of relevant primary research and News and Comment articles published by Nature Cancer.
Cancer therapies have evolved considerably in recent decades, substantially improving the quality of life and survival of patients with cancer. In this issue, we launch our Series on Cancer Therapy, exploring current paradigms and recent advances and challenges in this field, through specially commissioned articles.
Melenhorst and colleagues review the current status of chimeric antigen receptor T cell therapies, focusing on the rapid progress achieved in this area of immunotherapy, but also the challenges to be overcome.
Scatiltri and colleagues review the paradigms of targeting PI3K in solid tumors in the clinic, including the progress so far in developing effective inhibitors as well as clinical limitations due to toxicity and therapeutic resistance.
Passaro and colleagues discuss recent advances in treating EGFR-mutant lung cancer, including methods for detecting disease and tracking therapy response, developments in understanding of resistance mechanisms and ongoing clinical trials to circumvent therapeutic resistance to EGFR targeting.
Mukhopadhyay, Vander Heiden and McCormick review the metabolic landscape of RAS-driven cancers, the effects of RAS-directed metabolic reprogramming and opportunities for targeting these cancers therapeutically.
The deployment of molecular biomarkers that are indicative of sensitivity to tumor-targeted or immune-targeted cancer therapies improves the outcome of individual patients and increases the chances of successful drug approval. However, for many lethal malignancies, the majority of clinical trials are conducted with patients who do not have biomarkers and hence they miss the target.
KRAS mutations are among the most prevalent tumor drivers, but targeting them pharmacologically has been challenging. Recent landmark studies have demonstrated promising clinical results of KRASG12C inhibition by using small molecules. Bar-Sagi, and Knelson and Sequist provide their distinct perspectives on this recent tour de force in targeting KRASG12C alterations.
Beyond the suffering caused by the disease, most patients diagnosed with cancer in the USA face substantial financial hardships associated with their treatments. What underlies the financial toxicity of cancer?
Precision oncology trials based on cancer biomarkers have the potential to improve outcomes by guiding the optimal choice of therapies for patients. For this to be truly achieved, computational methods such as virtual molecular tumor boards, dynamic precision medicine and digital twins are needed to support cohort selection and trial enrollment at scale.
Although RET alterations are relatively frequent across tumor types, specific targeting of RET in the clinic has been challenging. Ambrogio, Aggarwal and colleagues provide their views on how mechanistic studies have swiftly translated into powerful targeted therapies in two recent clinical studies that led to the FDA approval of selpercatinib for certain tumors in which RET is altered.
The risks posed to patients with cancer by the current COVID-19 pandemic demand rapid structural changes in healthcare delivery, with many positive changes likely to continue long term. An immediate critical reassessment of trial methodology based on clinical and scientific priorities is essential to ensure the resilience of clinical cancer research and optimize patient-centered care.
Obenauf and colleagues report that acquired resistance to BRAF and MEK inhibitors in melanoma confers cross-resistance to immune checkpoint blockade by fostering a cancer cell–instructed, immune-evasive tumor microenvironment.
D’Andrea and colleagues identify the antibiotic novobiocin as a specific POLQ inhibitor with preclinical activity in homologous-recombination-deficient breast and ovarian tumors in vivo, including these with acquired PARP inhibitor resistance.
Yang and colleagues perform a network system–pharmacology approach and clinical data integration, and identify LCK and BCL2 signaling as the molecular determinants of dasatinib response in pediatric and adult patients with T-ALL.
Bhardwaj et al. report that adding Flt3 ligand to the treatment strategy effectively increased DC populations and increased T-cell responses in a randomized phase II trial of a DC-targeted vaccine for the melanoma antigen NY-ESO-1.
Quezada and colleagues develop improved anti-CD25 antibodies that preserve IL-2 signaling and enhance single-agent antitumor immunity and immunotherapy through specific and efficient Treg cell depletion.
Ma et al. apply few-shot learning to train a neural network model on cell-line drug-response data, and they subsequently transfer it to distinct biological contexts including different tissues and patient-derived tumor cells and xenografts.
Ishikawa and colleagues perform integrated genomic and drug-sensitivity screens with extensive PDX modeling and reveal combined XIAP and BCL2 inhibition as a vulnerability hub across AML genetic alterations.
Eilers and colleagues report that Aurora-A suppresses transcription–replication conflicts in MYCN-driven neuroblastoma, a vulnerability that can be targeted with a combination of Aurora-A and ATR kinase inhibitors.
Zhang and colleagues analyzed data from patient samples exposed to the BCL2 inhibitor venetoclax, approved for treatment of acute myeloid leukemia, identifying modes of therapy resistance and synthetic lethality with MCL1 inhibition.
Ferrando and colleagues analyze matched diagnostic and relapsed acute lymphocytic leukemia by whole-genome sequencing, and perform in vitro genome-wide CRISPR screens, to examine alterations associated with chemotherapy resistance.