Update on cancer therapeutics最新文献

Advances in colorectal cancer therapy, especially, advantages in combination of biologic and cytotoxic chemotherapy, have made the diagnoses and management of the disease to a complete different level. Encouraging development has been developed in the treatment of hepatocellular carcinoma. However, treatment of pancreatic and biliary cancer is still a major challenging for oncologists.

The RAS/RAF/MEK/ERK signaling pathway plays a central role in the regulation of many cellular processes including proliferation, survival, differentiation, apoptosis, motility and metabolism. This pathway is activated by a diverse group of extracellular signals including integrins, growth factor receptors [i.e. epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR)], or cytokines. While RAS, RAF and MEK activity appear restricted to only one class of substrates, ERK activates more than 70 substrates including nuclear transcription factors. Agents targeting the RAS/RAF/MEK/ERK pathway may therefore inhibit oncogenic signaling in tumor cells. However, most pharmacological agents directed against these targets have not been successful in the clinic. The only small molecule in this class to be approved for cancer therapy is sorafenib, which is not a pure RAF kinase inhibitor. To be successful, one may have to approach this pathway from a multi-pronged approach and also tailor therapy according to which component might be the one playing a pivotal role in a particular system. Relatively selective raf kinase inhibitors are entering clinical trials, and one MEK inhibitor, AZD6244 is in phase II clinical trials.

Antiandrogens are an important class of therapeutic agents for treatment of prostate cancer. While traditionally used as a second-line hormonal therapy following androgen deprivation treatment, they have been studied in a number of other settings. Antiandrogens continue to be a class of highly selective agents with relatively little toxicity compared to non-hormonal therapies for advanced disease. Compounds in development that target androgen receptor activation hold great promise for men with prostate cancer.

The cytotoxic T lymphocyte-associated protein 4 (CTLA4) is a main negative regulator of the immune system, which inhibits the costimulatory signaling for T cells. Preclinical studies demonstrated that antibodies against CTLA4-induced regression of some murine tumors. Two CTLA4-blocking monoclonal antibodies have entered clinical development and are currently in pivotal clinical trial testing. Ipilimumab (formerly MDX010) is an IgG1 and tremelimumab (formerly CP-675,206 and transiently ticilimumab), is an IgG2, both being fully human monoclonal antibodies. Across several early clinical trials, including dose escalation, single dose, multi-dose, and in combination with a variety of other immune stimulants like peptide vaccines or interleukin-2, objective tumor responses in patients with metastatic melanoma have been observed in the range of 5–22%. A key feature is that some of these responses are extremely long-lived responses, lasting years. The early clinical testing also demonstrated that these CTLA4-blocking antibodies can lead to significant toxicities, most with an inflammatory or immune-mediated mechanism of action. These include colitis and skin rash as the most common toxicities, and a variety of autoimmune and inflammatory processes against multiple organs. Some of these toxicities require immune suppressive therapy and may lead to permanent damage in occasional patients. In conclusion, two monoclonal antibodies blocking CTLA4 have demonstrated ability to break tolerance to self-tissues and result in long lasting objective cancer regressions, and have moved onto late stages of clinical development.

Many progresses have been made in the management of non-Hodgkin's lymphoma and Hodgkin's lymphoma. Newer chemotherapeutic regimens, extended use of PET to evaluate the stage and mainly the response after treatment, rituximab and other monoclonal antibodies, radioimmunoconjugates, and allogeneic stem cell transplantation, all contribute to a better treatment of these diseases. Furthermore, risk-adapted treatment can reduce late toxicities, such as cardiovascular disease, secondary myelodysplastic syndrome, and solid tumors.

The cell-surface molecule CD40, a member of the tumor necrosis factor receptor superfamily, broadly regulates immune activation and mediates tumor apoptosis. CD40 is expressed by antigen-presenting cells (APC) and engagement of its natural ligand on T cells activates APC including dendritic cells and B cells. Agonistic CD40 antibodies have been shown to substitute for T cell help provided by CD4+ lymphocytes in murine models of T cell-mediated immunity. In tumor-bearing hosts, CD40 agonists trigger effective immune responses against tumor-associated antigens. In contrast, CD40 is also expressed on many tumor cells and its ligation in this setting mediates a direct cytotoxic effect. Engagement of CD40 on tumor cells results in apoptosis in vitro and impaired tumor growth in vivo. These observations have prompted efforts to use agonistic CD40 antibodies for the treatment of cancer patients and initial clinical results have been promising.