Advances in Cancer Research

While immunotherapy and targeted therapies represent major advances against different types of malignancies, the mainstay of cancer therapy continues to be radiation and surgery for localized disease, and chemotherapy for systemic disease, with the preponderance of chemotherapeutic agents (such as anthracyclines, alkylating agents, and antimetabolites) having been developed decades ago. Combination chemotherapy regimens have changed the natural history of once deadly diseases such as breast and prostate cancer and led to curative regimens in advanced hematological malignancies and testicular cancer...

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Over the last couple of decades, it has become increasingly apparent that the tumor microenvironment (TME) mediates every step of cancer progression and solid tumors are only able to metastasize with a permissive TME. This intricate interaction of cancer cells with their surrounding TME, or stroma, is becoming more understood with an ever greater knowledge of tumor-stromal signaling pairs such as platelet-derived growth factors (PDGF) and their cognate receptors. We and others have focused our research efforts on understanding how tumor-derived PDGFB activates platelet-derived growth factor receptor beta (PDGFRβ) signaling specifically in the breast cancer TME...

In most solid tumors, malignant cells coexist with non-cancerous host tissue comprised of a variety of extracellular matrix components and cell types, notably fibroblasts, immune cells, and endothelial cells. It is becoming increasingly evident that the non-cancerous host tissue, often referred to as the tumor stroma or the tumor microenvironment, wields tremendous influence in the proliferation, survival, and metastatic ability of cancer cells. The tumor stroma has an active biological role in the transmission of signals, such as growth factors and chemokines that activate oncogenic signaling pathways by autocrine and paracrine mechanisms...

The tumor microenvironment contains a heterogeneous population of stromal and cancer cells that engage in metabolic crosstalk to ultimately promote tumor growth and contribute to progression. Due to heterogeneity within solid tumors, pooled mass spectrometry workflows are less sensitive at delineating unique metabolic perturbations between stromal and immune cell populations. Two critical, but understudied, facets of glucose metabolism are anabolic pathways for glycogen and N-linked glycan biosynthesis. Together, these complex carbohydrates modulate bioenergetics and protein-structure function, and create functional microanatomy in distinct cell populations within the tumor heterogeneity...

Decades of research have concluded that disruptions to Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) have profound effects on cancer progression. However, as our understanding of the tumor stroma has evolved, we can appreciate that disruptions to tumor suppressors such as PTEN should not be studied solely in an epithelial context. Inactivation of PTEN in the stroma is associated with worse outcomes in human cancers, therefore, it is important to understand activities regulated downstream of PTEN in stromal compartments...

Pancreas and breast cancers both contain abundant stromal components within the tumor tissues. A prominent cell type within the stroma is cancer-associated fibroblasts (CAFs). CAFs play critical and complex roles establishing the tumor microenvironment to either promote or prevent tumor progression. Recently, complex genetic models and single cell-based techniques have provided emerging insights on the precise functions and cellular heterogeneity of CAFs. The transformation of normal fibroblasts into CAFs is a key event during tumor initiation and progression...

Cancer is a complex disease and a significant cause of mortality worldwide. Over the course of nearly all cancer types, collagen within the tumor microenvironment influences emergence, progression, and metastasis. This review discusses collagen regulation within the tumor microenvironment, pathological involvement of collagen, and predictive values of collagen and related extracellular matrix components in main cancer types. A survey of predictive tests leveraging collagen assays using clinical cohorts is presented...

As part of the connective tissue, activated fibroblasts play an important role in development and disease pathogenesis, while quiescent resident fibroblasts are responsible for sustaining tissue homeostasis. Fibroblastic activation is particularly evident in the tumor microenvironment where fibroblasts transition into tumor-supporting cancer-associated fibroblasts (CAFs), with some CAFs maintaining tumor-suppressive functions. While the tumor-supporting features of CAFs and their fibroblast-like precursors predominantly function through paracrine chemical communication (e...

Carcinoma is defined as cancer arising from the epithelial cells that line an organ or tissue. The most common carcinoma in males arises in the prostate and breast in females; while the most significant cause of cancer related mortality in the United States is carcinoma of the lung. Cancers typically begin as a clonal proliferation of cells that have acquired distinct mutations, which then progress to invasive carcinoma as the cells breach the underlying basement membrane associated with the tissue of origin...

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Disruption of the native membrane organization of Ras by the farnesyltransferase inhibitor tipifarnib in the late 1990s constituted the first indirect approach to drug target Ras. Since then, our understanding of how dynamically Ras shuttles between subcellular locations has changed significantly. Ras proteins have to arrive at the plasma membrane for efficient MAPK-signal propagation. On the plasma membrane Ras proteins are organized into isoform specific proteo-lipid assemblies called nanocluster. Recent evidence suggests that Ras nanocluster have a specific lipid composition, which supports the recruitment of effectors such as Raf...

The RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and capillary malformation-arteriovenous malformation syndrome...

The RAS family of small GTPases are among the most frequently mutated oncogenes in human cancer. Approximately 20% of cancers harbor a RAS mutation, and >150 different missense mutations have been detected. Many of these mutations have mutant-specific biochemical defects that alter nucleotide binding and hydrolysis, effector interactions and cell signaling, prompting renewed efforts in the development of anti-RAS therapies, including the mutation-specific strategies. Previously viewed as undruggable, the recent FDA approval of a KRASG12C -selective inhibitor has offered real promise to the development of allele-specific RAS therapies...

RAS mutations are among the most frequent oncogenic drivers observed in human cancers. With a lack of available treatment options, RAS-mutant cancers account for many of the deadliest cancers in the United States. Recent studies established that altered metabolic requirements are a hallmark of cancer, and many of these alterations are driven by aberrant RAS signaling. Specifically, RAS-driven cancers are characterized by upregulated glycolysis, the differential channeling of glycolytic intermediates, upregulated nutrient scavenging pathways such as autophagy and macropinocytosis, and altered glutamine utilization and mitochondrial function...

RAS proteins represent critical drivers of tumor development and thus are the focus of intense efforts to pharmacologically inhibit these proteins in human cancer. Although recent success has been attained in developing clinically efficacious inhibitors to KRASG12C , there remains a critical need for developing approaches to inhibit additional mutant RAS proteins. A number of anti-RAS biologics have been developed which reveal novel and potentially therapeutically targetable vulnerabilities in oncogenic RAS...

The non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) is a critical component of RAS/MAPK signaling by acting upstream of RAS to promote oncogenic signaling and tumor growth. Over three decades, SHP2 was considered "undruggable" because enzymatic active-site inhibitors generally showed off-target inhibition of other proteins and low membrane permeability. More recently, allosteric SHP2 inhibitors with striking inhibitory potency have been developed. These small molecules effectively block the signal transduction between receptor tyrosine kinases (RTKs) and RAS/MAPK signaling and show efficacy in preclinical cancer models...

RAS proteins play major roles in many human cancers, but programs to develop direct RAS inhibitors so far have only been successful for the oncogenic KRAS mutant G12C. As an alternative approach, inhibitors for the RAS guanine nucleotide exchange factor SOS1 have been investigated by several academic groups and companies, and major progress has been achieved in recent years in the optimization of small molecule activators and inhibitors of SOS1. Here, we review the discovery and development of small molecule modulators of SOS1 and their molecular binding modes and modes of action...

Mutations in the three RAS oncogenes are present in approximately 30% of all human cancers that drive tumor growth and metastasis by aberrant activation of RAS-mediated signaling. Despite the well-established role of RAS in tumorigenesis, past efforts to develop small molecule inhibitors have failed for various reasons leading many to consider RAS as "undruggable." Advances over the past decade with KRAS(G12C) mutation-specific inhibitors have culminated in the first FDA-approved RAS drug, sotorasib. However, the patient population that stands to benefit from KRAS(G12C) inhibitors is inherently limited to those patients harboring KRAS(G12C) mutations...

Mutational activation of the KRAS oncogene is found in ~95% of pancreatic ductal adenocarcinoma (PDAC), the major form of pancreatic cancer. With substantial experimental evidence that continued aberrant KRAS function is essential for the maintenance of PDAC tumorigenic growth, the National Cancer Institute has identified the development of effective anti-KRAS therapies as one of four major initiatives for pancreatic cancer research. The recent clinical success in the development of an anti-KRAS therapy targeting one specific KRAS mutant (G12C) supports the significant potential impact of anti-KRAS therapies...