Preclinical and early clinical trials indicate synthetic oligodeoxynucleotides containing unmethylated CG dinucleotides (CpG ODN) have potent immunostimulatory effects and can enhance the anti-cancer activity of a variety of cancer treatments. Synergy between CpG ODN and monoclonal antibodies has been noted in various preclinical models. Early clinical trials indicate CpG ODN and monoclonal antibodies can be administered safely together. Preclinical models indicate CpG ODN can enhance the anti-tumor activity of both chemotherapy and radiation therapy. Thus, one possible approach to the use of CpG ODN was to use it in combination with cytotoxic chemotherapy with the goal of enhancing presentation of tumor antigen from dying cancer cells. Promising results in a randomized phase II trial in patients with non-small cell lung cancer led to initiation of two large randomized phase III trials comparing CpG ODN plus chemotherapy to chemotherapy alone. Unfortunately, interim analysis of these trials indicated CpG ODN was unlikely to enhance efficacy of chemotherapy, and they were stopped. CpG ODN also holds promise as a component of cancer vaccines including those composed of protein antigen, peptides, whole tumor cells, and antigen-pulsed dendritic cells. Finally, CpG ODN has been combined with a variety of cytokines to enhance NK activation, promote development of an active anti-tumor immune response or induce apoptosis of malignant cells that express the TLR9 receptor. Overall, both preclinical and early clinical trials suggest CpG ODN may be a valuable component of a variety of approaches to cancer therapy. However, clinical development of this recently discovered, novel class of immunostimulatory agents is just beginning, and we still have much to learn about the optimal approach to their use, and their potential.
Topoisomerase II is an enzyme essential for DNA replication, chromosome condensation and chromosome segregation. Inhibitors of topoisomerase II are important drugs used in the therapy of many neoplasms including breast cancer, lung cancer, testicular cancer, lymphomas and sarcomas. This paper reviews the mechanism of action, toxicities, pharmacology and clinical use of topoisomerase II inhibitors including etoposide, teniposide, doxorubicin, daunorubicin, epirubicin, idarubicin and mitoxantrone. New information regarding these agents and on topoisomerase II inhibitors under development is highlighted.
This article reviews recent preclinical and clinical advances in the use of pretargeting methods for the radioimmunodetection and radioimmunotherapy of cancer. Whereas directly labeled antibodies, fragments, and subfragments (minibodies and other constructs) have shown promise in both imaging and therapy applications over the past 25 years, their clinical adoption has not fulfilled the original expectations due to either poor image resolution and contrast in scanning or insufficient radiation doses delivered selectively to tumors for therapy. Pretargeting involves the separation of the localization of tumor with an anticancer antibody from the subsequent delivery of the imaging or therapeutic radionuclide. This has shown improvements in both imaging and therapy by overcoming the limitations of conventional, or one-step, radioimmunodetection or radioimmunotherapy. We focus herein on the use of bispecific antibodies followed by radiolabeled peptide haptens as a new modality of selective delivery of radionuclides for the imaging and therapy of cancer. Our particular emphasis in pretargeting is the use of bispecific trimeric (three Fab′s) recombinant constructs made by a modular method of antibody and protein engineering of fusion molecules called dock and lock (DNL).
The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) have been implicated in transformation of a variety of malignancies. Chronic or dysregulated activation of the MET/HGF pathway may lead to increased cell growth, invasion, angiogenesis, and metastasis, reduced apoptosis, altered cytoskeletal functions and other biological changes. It has been suggested that ligand activated MET stimulation can be sufficient for a transforming phenotype. In addition, amplification and activation mutations (germline and/or somatic) within the tyrosine kinase domain, juxtamembrane domain, or semaphorin domain have been identified for MET. MET gain-of-function mutations lead to either deregulated or prolonged tyrosine kinase activity, which are instrumental to its transforming activity. A number of therapeutic strategies targeting ligand-dependent activation or the kinase domain have been employed to inhibit MET. The different structural requirements for activation of signaling events and biological functions regulated by MET will be summarized. Therapeutic targets and current pre-clinical and clinical approaches will be described. Targeting the HGF/MET pathway, alone or in combination with standard therapies, is likely to improve present therapies in MET-dependent malignancies.
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 and impaired tumor growth . These observations have prompted efforts to use agonistic CD40 antibodies for the treatment of cancer patients and initial clinical results have been promising.
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.
Angiogenesis plays a crucial role in the survival, proliferation, and metastatic potential of several tumors, including genitourinary (GU) cancers. Over the last decade, increasing basic science and clinical research have led to the approval of several angiogenesis inhibitors. GU tumors are unique in its pathogenesis whereby specific pathways, such as involvement of the Von Hippel-Lindau gene in clear cell renal cell cancer and aberrant overexpression of vascular endothelial growth factor in prostatic cancers and transitional cell bladder cancers, allow for potential targeting using angiogenesis inhibitors. This review discusses the biologic pathways as well as the rationale for using angiogenesis inhibitors in renal cell, prostate, and transitional cell bladder cancers. This review also focuses on pivotal trials and emerging data on the use of these inhibitors.
Drugs that target tubulin, including the vinca alkaloids and taxanes, represent some of the most effective anticancer medications. Both natural-product and semisynthetic compounds show a remarkable spectrum of anticancer activity. In this chapter, we review new developments in cancer biology and pharmacology that shed light on the effectiveness of tubulin binding agents. In addition, we highlight newer agents and several drugs in preclinical development that hold considerable promise for the future. Finally, we comment on the rational selection of patients for chemotherapy and a more mechanistic approach to using these drugs in combinations.
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.
Epithelial ovarian cancer, the fourth leading cause of cancer deaths in American women, is a devastating disease. Although the combined intraperitoneal and intravenous administration of first-line chemotherapy does produce some improvement in patient outcomes in comparison with intravenous administration alone, the results of completed clinical trials suggest that a plateau has been reached in the benefits that can be achieved with cytotoxic chemotherapy alone in ovarian cancer. Epithelial ovarian cancer is currently classified by surgical and histologic criteria. However, the predictive value of this classification is limited. Moreover, the complexity of the different subtypes of ovarian cancer presents challenges to our understanding of the origin and pathogenesis of this disease. The sequential acquisition of molecular anomalies as occurs in colorectal carcinogenesis has not been described for ovarian cancer. However, increasing evidence indicates that multiple genetic and epigenetic events contribute to epithelial ovarian carcinogenesis. These events include aberrations in the expression of patterning genes, genomic instability, and resultant chromosomal changes, and may be triggered by excessive exposure of surface epithelial cells to autocrine/paracrine stimulation by sex steroids and other growth factors. As the disease progresses, activation of kinase pathways and continued abnormal autocrine/paracrine stimulation contribute to genomic instability and chemoresistance but also identify novel potential targets for therapeutic intervention. Although the list of genomic and other aberrations in ovarian cancer is daunting, a systems approach and the integration of therapies targeting multiple component ‘driver’ genes of important genetic aberrations has potential in treatment and for potentiation of cytotoxic chemotherapy efficacy.
Breast cancer treatment has evolved dramatically in the last few years. Despite the benefit of anthracyclines, taxanes and trastuzumab for patients with metastatic and early breast cancer, the challenges of de novo and acquired resistance are still present. With advances in the molecular characterization of breast cancer, patient selection and individualization of treatment has taken on singular importance. Three main types of breast cancer have been reported to date: (a) HER-2 positive; (b) basal-like; and (c) luminal breast cancer. A large number of new agents now target different receptors and signalling pathways that sustain cancer survival and proliferation. In this review we highlight the novel molecules currently being tested in clinical trials that have or will have the potential to change our daily clinical practice; in particular, we focus on molecules used in the treatment of HER-2 positive and basal-like breast cancer patients.
Preclinical and clinical investigations currently underway are employing novel strategies for combining vaccines with conventional and experimental anticancer therapies. To date, the FDA has not approved a therapeutic cancer vaccine. However, the results of recent investigations suggest an increasing role for vaccines in new models of combination therapy for many types of cancer. This article reviews and discusses therapeutic cancer strategies that employ vaccines in combination with local radiation, chemotherapy, hormone therapy, and anti-CTLA-4 mAb. Preclinical studies have shown that certain anticancer agents have immune modulatory effects that result in up-regulation of surface expression of MHC molecules, tumor-associated antigens, or Fas on malignant cells, rendering them more susceptible to immune destruction. Preliminary results of clinical studies using combination strategies have demonstrated a postvaccination antigen cascade, prolonged time to disease progression, and improved overall survival. Several larger randomized trials are ongoing, and more are required to support these findings.
Treatment for metastatic castration resistant prostate cancer (CRPC) represents a critical need. While docetaxel-based chemotherapy has been shown to extend life, relieve pain, and improve the quality of life expanded treatment options are necessary. No standard second line therapy exists and secondary hormonal manipulations before and after docetaxel offer marginal benefits. The increased understanding of the mechanisms of progressive castration resistant prostate cancer has translated into an increasing pipeline of novel therapies such as vaccines, monoclonal antibodies, bone-targeted drugs, antisense oligonucleotides, anti-angiogenic drugs, small molecule receptor tyrosine kinase inhibitors and more specific targets of the androgen receptor. The future treatment for the most advanced prostate cancer patients is encouraging with broadened clinical benefit.
Traditional treatment options for bladder cancer include transurethral resection and intravesical Bacillus Calmette Guerin for early stage disease and cystectomy or radiation therapy (with or without chemotherapy) for muscle-invasive disease. Platinum-based chemotherapy improves patient outcomes in both the perioperative and metastatic setting. Despite an increase in new therapeutic options over the past decade for many cancer patients, similar advances in bladder cancer are limited. In recent years, an improved understanding of the molecular forces driving bladder cancer development and progression has unfolded. These discoveries create a set of innovative therapeutic opportunities in bladder cancer. This review examines novel anti-cancer agents currently in clinical trials with preclinical rationale to support evaluation in bladder cancer. In addition, strategies to match a patient's tumor to the most appropriate agent are discussed. This may provide a more rational approach to evaluating the role of emerging anti-cancer agents in bladder cancer.
The immunomodulatory drug class has a broad range of biological effects with applications both within and outside oncology, and the oral bioavailability of these compounds makes them attractive agents. Thalidomide, the parent compound, was introduced into oncology over a decade ago to test many of its interesting pre-clinical features. While activity was notable in multiple myeloma, there were signals of activity in other malignancies. Multiple combinations have been developed and tested both in relapsed and front-line treatment of multiple myeloma. Based on modifications of the original drug, two derivatives, lenalidomide and pomalidomide, were developed and have been tested clinically. Lenalidomide is more potent than thalidomide and has demonstrated significant activity in multiple myeloma as well as myelodysplastic syndromes. Clinical activity has been noted in other malignancies too suggesting a broader range of activity. Multiple combinations have been tested as well in the relapsed and upfront setting. Pomalidomide demonstrated increase potency as well and has just begun early phase clinical testing.
Although most patients with thyroid cancer do well with traditional therapy, some will go on to develop progressive disease. In the past, few effective treatment options were available for patients with metastatic thyroid carcinoma. However, advances in our understanding of the molecular basis of thyroid cancer initiation and progression have led to many new potential therapies targeted at specific molecular pathways. Many of these novel compounds have been evaluated in cell lines, animal models, and recently, in clinical trials. This review will focus on new potential therapies in the treatment of progressive thyroid cancer, with an emphasis on the activity of these agents in the clinical arena.
Adoptive T-cell therapy is an attractive option for targeting tumors associated with Epstein-Barr virus. In immunogenic Type III latency tumors such as post transplant lymphoproliferative disease, EBV-specific CTL have been used successfully as prophylaxis and treatment. In Type II latency malignancies such as Hodgkin's disease and nasopharyngeal cancer, a more restricted array of EBV antigens are encoded and the clinical response rates after infusion of EBV-specific CTLs have been lower. Current strategies to increase response rates include targeting CTL to subdominant EBV antigens and genetically modifying CTL to increase their potency.