Prostate cancer is one of the most common forms of cancer that affects the prostate gland in the male urogenital tract. Most prostate cancers are slow growing and are detected in individuals older than age 50. Although environmental factors contribute to the development of prostate cancer, risk is significantly associated with incidence among first-degree relatives. In recent years, several inherited and spontaneously mutated genes have been linked to prostate cancer. Here we highlight these findings and how they provide insight into the development of targeted prostate cancer therapies.
Ovarian cancer remains one of the leading causes of mortality for women with gynecological cancers and continues to be associated with stubbornly low 5-year survival rates. Depending on the stage or type of ovarian cancer, localized treatments including surgical resection or radiation may be sufficient. Treatment of metastatic ovarian cancer may include surgery and radiation combined with chemotherapy. Hormone therapy is also typically combined with chemotherapy for targeted reduction of estrogen and/or stimulation of progesterone for the targeted treatment of ovarian stromal tumors that produce high levels of estrogen. Nonetheless, many of these treatments have limited efficacy for treating metastatic ovarian cancer.
Sarcomas are a group of aggressive heterogeneous tumors for which more than 100 histological subtypes have been defined1. Sarcomas are found in a variety of solid tissues, including bone and gastrointestinal stromal cells. Current treatment options include radiotherapy, surgical resection, targeted therapies, and chemotherapy, but these treatments have had limited efficacy on intermediate to high grade tumors. Investigations into the molecular and cellular mechanisms that drive sarcomas have helped identify potential biomarkers that can serve as potential therapeutic targets. In addition, recent studies have also focused on the tumor microenvironment (TME) within sarcomas and the roles of different immune cell subsets creating an immunosuppressive microenvironment. These observations directly inform novel immunotherapeutic approaches that are being examined in preclinical and clinical studies.
Gastrointestinal cancers are a heterogeneous group of cancers that can be caused by H. pylori bacterial or Epstein-Barr virus infection, chronic inflammation, or inherited or spontaneous genetic mutations. Advances in solid tumor immunotherapy for gastrointestinal cancers includes the development of methods that improve the screening, evaluation, and development of more precise and robust treatments. Breakthroughs in basic and translational research are leading to better treatment options for gastrointestinal cancer, and CRISPR/Cas9-based (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) gene editing technology is at the forefront of these discoveries.
Bladder cancer is a relatively common form of cancer that is defined as either pre-invasive or invasive, and non-muscle invasive bladder cancer (NMIBC) is the most-commonly diagnosed subtype. NMIBC is typically treated by surgical resection and/or intravesical delivery of chemo- or immunotherapy-based adjuvant treatment, and long-term efficacy is monitored by urine testing or cystoscopy. Muscle-invasive bladder cancer (MIBC) is relatively resistant to current treatment options and occurs more frequently in men. MIBC also has high rates of morbidity and mortality, and novel therapies or combination therapies area being developed to better treat this form of bladder cancer.
Here we highlight recent findings about invasive bladder cancer biology and how these observations are informing the development of new therapies.
Glioblastoma multiforme (GBM) is an aggressive form of primary malignancy of the central nervous system (CNS) that causes brain tumors. GBM has been associated with poor prognoses and high mortality rates and a 5-year relative survival rate ranging from 6-22% percent depending on age of onset. Currently, standard-of-care treatments include cytoreductive surgery followed by chemoradiotherapy, but these are not considered curative treatments, and efficacy varies widely between patients. Temozolomide is a DNA alkylating agent prodrug commonly used for adjuvant chemotherapy in GBM, but treatment resistance is a common occurrence, and this drug is also associated with clinically significantly toxicity.
Head and neck squamous cell carcinoma (HNSCC) is one of the most common forms of cancer in the world. This heterogeneous disease is most often seen in men and is closely linked to tobacco usage, which can be enhanced by alcohol usage. Human papillomavirus (HPV) infection is an independent risk factor for HNSCC. Most HPV- HNSCCs occur in the larynx and oral cavity, and HPV+ HNSCCs typically arise in the oropharynx. Both HPV+ and HPV- HNSCCs are typically diagnosed at advanced disease stages and are often treated with an aggressive combination of surgery, radiotherapy (RT), and chemotherapy. More recently, cetuximab, an IgG1 monoclonal antibody that targets epidermal growth factor receptor (EGFR) has been used in combination with radiotherapy and has shown some improvements in progression-free survival (PFS) and overall survival (OS).
Melanoma broadly defines cancers that originate in melanocytes in the skin, eye, and inner ear. Cutaneous malignant melanoma is one of the most aggressive and fatal forms of this disease, but advances in immuno-oncology have dramatically improved outcomes1. Advances in cancer genomics have been critical to evaluating which mutations are involved in a shift toward metastasis and have been valuable to informing treatment options using novel inhibitors that target specific gene mutations. Here we highlight mutations that are critical to tumor formation and metastasis and feature immuno-oncology treatments that are in use or being evaluated as individual or combination treatments.
Renal cell carcinoma (RCC) is a common cancer of the genitourinary tract that has very poor survival outcomes if metastatic. RCC is now understood to be composed of several different types of cancer with different genetic features and varied clinical responses. Histological diagnosis has been the primary method to diagnose RCC and has been used to define three major RCC subtypes, including the most common subtype, clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (PRCC; further divided into two subtypes), and chromophobe renal cell carcinoma (ChRCC). More recent comparative genomic and phenotypic analysis has identified mutations and epigenetic modifications associated with different histological subtypes. Across all subtypes, increased DNA hypermethylation and gene alterations in CDKN2A were associated with a poor prognosis as was an increased Th2 immune gene signature. For ccRCC, increased levels of mRNA transcripts associated with ribose metabolism and the immune response were associated with poor survival. ccRCC is also defined by the early loss of chromosome 3p, which in turn causes a loss of heterozygosity for the VHL, PBRM1, SETD2, and BAP1 tumor suppressor genes and subsequent mutation of these genes that leads to tumorigenesis. There is also a subset of ChRCC with a unique metabolic expression pattern that is associated with extremely poor survival2. PRCC can be classified as type 1, for which PBRM1 mutations are linked to poor survival but type 2 PRCC has increased expression of glycolysis and metabolism related mRNA transcripts2.
Biliary tract cancers, which are also known as cholangiocarcinomas (CCA), describe malignancies that occur in the biliary tract and include the pancreas, gallbladder and bile ducts. These are relatively rare cancers but are associated with a poor prognosis given that these cancers are difficult to detect and are usually diagnosed at later stages of disease. Histologically, CCAs are predominantly adenocarcinomas and are classified by growth patterns (mass forming, intraductal, or periductal) and anatomical locations (intrahepatic, perihilar, or distal), and mixed hepatocellular CCAs are defined as a separate subtype of primary hepatic cancer1.