Olaparib for the treatment of epithelial ovarian cancer

Introduction: Despite recent advances in the management of epithelial ovarian cancer, overall survival rates remain poor, and there is a pressing need to develop novel therapeutic agents and maintenance strategies to improve outcomes for women with this disease. Olaparib, a potent oral poly(ADP-ribose) polymerase (PARP) inhibitor, has demonstrated antitumor activity in women with ovarian cancer, associated with homologous recombination deficiency.

Areas covered: This review outlines the rationale for PARP inhibitor therapy in ovarian cancer and summarizes the efficacy and tolerability data for olaparib to date. Ongoing phase III clinical trials of olaparib in ovarian cancer will be discussed.

Expert opinion: There are a number of issues regarding the optimal use of olaparib in ovarian cancer, including the identification of a homologous recombination deficiency signature to predict treatment response, establishment of the optimal treatment setting (maintenance or relapsed disease), and evaluation of cost-effectiveness. Finally, the long term consequences of PARP inhibitors, including the risk of myelodysplasia and acute myeloid leukemia need to be quantified in ongoing large phase III clinical trials.     

Poly-ADP-ribose polymerases (PARPs) as a therapeutic target in the treatment of selected cancers

ABSTRACT

Introduction: The implementation of poly-ADP-ribose polymerase (PARP) inhibitors for therapy has created potential treatments for a wide spectrum of malignancies involving DNA damage repair gene abnormalities. PARPs are a group of enzymes that are responsible for detecting and repairing DNA damage and therefore play a key role in maintaining cell function and integrity. PARP inhibitors are drugs that target DNA repair deficiencies. Inhibiting PARP activity in cancer cells causes cell death.

Areas covered: This review summarizes the role of PARP inhibitors in the treatment of cancer. We performed a systematic literature search in February 2019 in the electronic databases PubMed and EMBASE. Our search terms were the following: PARP, PARP inhibitors, PARPi, Poly ADP ribose polymerase, cancer treatment. We discuss PARP inhibitors currently being investigated in cancer clinical trials, their safety profiles, clinical resistance, combined therapeutic approaches and future challenges.

Expert Opinion: The future could bring novel PARP inhibitors with greater DNA trapping potential, better safety profiles and improved combined therapies involving hormonal, chemo-, radio- or immunotherapies. Progress may afford wider indications for PARP inhibitors in the treatment of cancer and the utilization for cancer prevention in high-risk mutation carriers. Research efforts should focus on identifying novel drugs that target DNA repair deficiencies.     

Investigational therapies for squamous cell lung cancer: from animal studies to phase II trials

Introduction: It remains challenging to treat squamous cell lung cancer (SCC) with limited therapeutic options. However, recent breakthroughs in targeted therapies and immunotherapies have shed some light on the management of this deadly disease.

Areas covered: The article first reviews the current treatment options for advanced SCC, especially recent FDA approved molecular agents (afatinib, ramucirumab and necitumumab) and immunotherapies (nivolumab, pembrolizumab and atezolimumab). We then provide an overview on investigational therapies with data ranging from preclinical to phase II studies, focusing on new cytotoxic agents, emerging molecularly targeted agents (including a PARP inhibitor for Homologous Recombinant Deficiency positive SCC) and novel immunotherapeutic strategies.

Expert opinion summary: Identification of potential therapeutic targets, development of novel clinical trials and the rapid approvals of immune checkpoint inhibitors have shifted the management paradigm for squamous cell lung cancer. On the other hand, continued efforts are needed to identify the predictive biomarkers and to investigate novel mechanistically-driven mono- and combination therapies. We need to learn more about the biology behind immune checkpoint blockade and tumor genomics in SCC for better patient selection and future trial design.     

DNA synthesis inhibitors for the treatment of gastrointestinal cancer

Introduction: Intensive laboratory, preclinical and clinical studies have identified and validated molecular targets in cancers, leading to a shift toward the development of novel, rationally designed and specific therapeutic agents. However, gastrointestinal cancers continue to have a poor prognosis, largely due to drug resistance.

Areas covered: Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.

Expert opinion: Conventional agents, including DNA synthesis inhibitors such as fluoropyrimidines and platinum analogs, remain the most effective therapeutics and are the standards against which new drugs are compared. Novel DNA synthesis inhibitors for the treatment of gastrointestinal malignancies include a combination of the antimetabolite TAS-102, which consists of trifluorothymidine with a thymidine phosphorylase inhibitor, and a novel micellar formulation of cisplatin NC-6004 that uses a nanotechnology-based drug delivery system. The challenges of translational cancer research using DNA synthesis inhibitors include the identification of drugs that are specific to tumor cells to reduce toxicity and increase antitumor efficacy, biomarkers to predict pharmacological responses to chemotherapeutic drugs, identification of ways to overcome drug resistance and development of novel combination therapies with DNA synthesis inhibitors and other cancer therapies, such as targeted molecular therapeutics. Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.     

The cancer stem cell paradigm: a new understanding of tumor development and treatment

Importance of the field: Cancer is the second leading cause of death in the United States, and therefore remains a central focus of modern medical research. Accumulating evidence supports a ‘cancer stem cell’ (CSC) model – where cancer growth and/or recurrence is driven by a small subset of tumor cells that exhibit properties similar to stem cells. This model may provide a conceptual framework for developing more effective cancer therapies that target cells propelling cancer growth.

Areas covered in this review: We review evidence supporting the CSC model and associated implications for understanding cancer biology and developing novel therapeutic strategies. Current controversies and unanswered questions of the CSC model are also discussed.

What the reader will gain: This review aims to describe how the CSC model is key to developing novel treatments and discusses associated shortcomings and unanswered questions.

Take home message: A fresh look at cancer biology and treatment is needed for many incurable cancers to improve clinical prognosis for patients. The CSC model posits a hierarchy in cancer where only a subset of cells drive malignancy, and if features of this model are correct, has implications for development of novel and hopefully more successful approaches to cancer therapy.     

Embracing synthetic lethality of novel anticancer therapies

Introduction: The significant challenge posed by cancer to human healthcare has led to the exploration of new approaches to combat it. Synthetic lethality (SL) is one such emerging area in the development of novel anticancer therapies. SL can be described as lethality (cell death) resulting from the combination of the two mutations, wherein the mutation in either of the two codependent genes in normal or cancer cells is viable. This concept is specifically being exploited in cancer research for selectively targeting specific tumor cells.

Areas covered: In this review, the authors summarize studies of SL-based novel anticancer therapies. The review highlights some of the selected advances in DNA damage response pathway-related SL pairs, particularly poly (ADP-ribose) polymerase (PARP) and SL pairs involved in mitochondrial death signaling pathways published in the last 3 years.

Expert opinion: Most of the currently used chemotherapeutic agents will destroy cells irrespective of whether they are cancer cells or fast growing normal cells; but SL is one of the approaches being developed with potential as a selective cancer therapy. PARP inhibitors, such as olaparib, are useful in BRCA mutated cancer cells and are also used in combination with other drug to enhance their efficacy. Research on PARP inhibitors is progressing at a good pace but there are still some significant challenges that must be addressed.     

State of the art and up-and-coming angiogenesis inhibitors for ovarian cancer

ABSTRACT

Angiogenesis inhibitors have clearly shown activity in ovarian cancer in various settings; however, preliminary data did not reflect significant survival benefit. Bevacizumab has been extensively studied and is approved for use in ovarian malignancy. However, the efficacy of bevacizumab is modest and most treated patients eventually develop acquired resistance, which highlights the need for new targeted therapies and/or combination strategies. Newer therapies are being evaluated and their role of these newer therapies is upcoming and promising. Recent research focuses on the role of this drug group in frontline, maintenance and recurrent settings. Combination of PARP inhibitors with angiogenesis inhibitors has recently shown to improved survival rates. Potential strategies need to be devised for selecting patients most likely to benefit from such therapy.     

Recent understanding of the molecular mechanisms for the efficacy and resistance of EGF receptor-specific tyrosine kinase inhibitors in non-small cell lung cancer

Introduction: The epidermal growth factor receptor (EGFR) and its family members are involved in many aspects of tumor biological processes. Aberrant activation of the EGFR tyrosine kinase by mutations or protein overexpression is observed in various types of human cancer, including lung cancer. EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, are highly effective in lung cancer patients who harbor active mutations in the EGFR gene. However, patients who are initially sensitive to EGFR-TKIs eventually relapse within few years.

Areas covered: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and is associated with a high frequency of EGFR mutations. This review describes the EGFR mutations that determine the sensitivity to EGFR-TKIs and the current understanding of the molecular mechanisms of acquired resistance to EGFR-TKIs in NSCLC. Furthermore, the authors describe recent strategies developed to overcome acquired resistance using second-generation EGFR-TKIs and combination therapies with several molecular-targeting drugs.

Expert opinion: Although recent findings have contributed to our understanding of the mechanism of acquired resistance and helped the development of novel strategies to overcome such resistance, the underlying mechanisms are complex and additional research is necessary to develop effective therapeutic strategies for individual patients with lung cancer.     

Advances in PARP inhibitors for the treatment of breast cancer

Introduction: Poly(ADP-Ribose) polymerases (PARPs) are one of the important components of base excision repair pathway for single strand DNA breaks. Currently accepted hypothesis for the mechanism of action for PARP inhibitors in tumors with homologous recombination deficiency is synthetic lethality, as the simultaneous blockage of both pathways prevents the tumor cells from repairing DNA damage. Other proposed mechanisms include PARP trapping, defective BRCA1 and POLQ recruitment to sites of DNA repair. Breast cancer subgroups with germline BRCA mutations or non-mutational functional defects in BRCA proteins exemplify potential targets for PARP inhibitors.

Areas covered: Promising results have been achieved with PARP inhibitors in BRCA associated cancers, particularly in ovarian and breast cancer. Olaparib is the only PARP inhibitor approved by FDA in the treatment of patients with germline BRCA mutated advanced ovarian cancer pretreated with ≥3 prior lines of chemotherapy. In this article, we reviewed the current status of PARP inhibitors, completed and ongoing trials, safety and resistance issues in patients with breast cancer.

Expert opinion: PARP inhibitors show promise in cancers with BRCA mutation and in the treatment of sporadic cancers with defective homologous recombination. Predictors of response, strategies to overcome resistance, combination with other chemotherapies and targeted agents, optimum dose and schedule of administration should be investigated in future trials.     

Targeting miR-21 in glioma: a small RNA with big potential

Importance of the field: Glioma therapies have produced relatively small improvements over the past decade, highlighting an important need to identify novel ways to target this disease. Targeted therapies against single activated protein kinases have proven effective in some cancers including gastrointestinal stromal cancer and colon cancer, but not yet in gliomas where multiple pathways and targets may be involved. MicroRNAs are emerging as key regulators of multiple pathways involved in cancer development and progression and may become the next targeted therapies in glioma.

Areas covered in this review: This review covers the basics of microRNA biology and specifically focuses on the roles of miR-21 in glioma and its potential as target for glioma therapy.

What the reader will gain: This review will provide the reader with an in depth understanding of how miR-21 functions in glioma. We also review the current state of studies designed to specifically target miR-21 as a potential future therapeutic.

Take home message: Identifying novel targets for the treatment of glioma is critical for advancing the current state of the field. MicroRNAs provide a novel target; and in glioma, targeting miR-21 may have broad consequences for the tumor that make it an attractive potential therapeutic.     

Emerging drugs for endometrial cancer

Introduction: From the dualistic classification that divides endometrial cancer (EC) into two types with distinct underlying molecular profiling, histopathology and clinical behavior, arises a deeper understanding of the carcinogenesis pathways. EC treatment comprises different and multimodal therapeutic approaches, such as chemotherapy, radiation therapy or combinations of novel drugs; however, few of these regimens have truly improved progression-free or survival rates in advanced and metastatic settings.

Areas covered: We reviewed the main molecular pathways involved in EC carcinogenesis through a wide literature search of novel compounds that alone or in combination with traditional drugs have been investigated or are currently under investigation in randomized clinical trials.

Expert opinion: The molecular therapies mainly discussed in this review are potential therapeutic candidates for more effective and specific treatments. In the genomic era, a deeper knowledge about molecular characteristics of cancer provides the hope for the development of better therapeutic approaches. Targeting both genetic and epigenetic alterations, attacking tumor cells using cell-surface markers overexpressed in tumor tissue, reactivating antitumor immune responses and identifying predictive biomarkers represent the emerging strategies and the major challenges.     

New agents for the management of resistant metastatic breast cancer

Introduction: Metastatic breast cancer (MBC) is an incurable disease and treatment is directed towards symptom palliation and survival prolongation. Treatment selection in patients is based on tumor biology, age, comorbidities, performance status, tumor burden, and prior treatment history.

Areas covered: This present review summarizes the recent treatment strategies in the management of MBC, highlighting regimens after first-line therapy. Topics discussed include new strategies for endocrine therapy, anti-HER2 therapy, and promising strategies for the management of triple negative breast cancer.

Expert opinion: MBC is a heterogeneous entity and despite recent advances, there is significant room for improvement of treatment beyond first-line therapies. Combination regimens that can maximize clinical efficacy while minimizing toxicities are required. Current investigation approaches in advanced stages of clinical development include immunoconjugates, immune checkpoint blockade, novel cyclin-dependent-kinase inhibitors, and PARP inhibitors for MBC associated with germline BRCA mutations. We recommend that every patient with MBC should be evaluated for clinical trial options.     

Safety profile of new anticancer drugs

Importance of the field: The development of targeted anticancer therapies stems from advances in molecular biology. New agents range from antibodies that form complexes with antigens on the surface of the cancer cell to small molecules that have been engineered to block key enzymatic reactions. The interaction of the antibody or drug with its target inhibits key pathways involved in cell proliferation or metastasis, or activates pathways leading to cell death. Such pathways constitute ideal pharmacological targets. Clinical benefits from these novel therapeutic strategies are striking for patients with metastatic diseases.

Areas covered: This review analyses the main toxicities among most common targeted therapies that have been approved by the FDA or European Medicines Agency for their clinical utilisation in solid tumours treatment.

What the reader will gain: Here, the main toxicity and safety data among new anticancer targeted therapies are described. Data are organised through the pathways targeted by the drugs.

Take home message: The emergence of new targeted anticancer therapies promises more efficient and less toxic therapies. Generally, they are well tolerated, toxicities are commonly mild to moderate and can be handled rapidly. However, if most of these adverse events are manageable, life threatening and fatal complications can still occur.     

Targeting embryonic signaling pathways in cancer therapy

Introduction: The embryonic signaling pathways (ESP), Hedgehog, Notch and Wnt, are critical for the regulation of normal stem cells and cellular development processes. They are also activated in the majority of cancers. ESP are operational in putative cancer stem cells (CSC), which drive initial tumorigenesis and sustain cancer progression and recurrence in non-CSC bulk subpopulations. ESP represent novel therapeutic targets. A variety of inhibitors and targeting strategies are being developed.

Areas covered: This review discusses the rationale for targeting ESP for cancer treatment, as well as specific inhibitors under development; mainly focusing on those approaching clinical use and the challenges that lie ahead. The data sources utilized are several database search engines (PubMed, Google, Clinicaltrials.gov), and the authors' involvement in the field.

Expert opinion: CSC research is rapidly evolving. Expectations regarding their therapeutic targeting are rising quickly. Further definition of what constitutes a true CSC, proper validation of CSC markers, a better understanding of cross-talk among ESP and other pathways, and interactions with tumor non-CSC and the tumor microenvironment are needed. The appropriate patient population, the right clinical setting and combination strategies to test these therapies, as well as the proper pharmacodynamic markers to measure, need to be further established.     

Therapeutic targeting and patient selection for cancers with homologous recombination defects

Introduction: DNA double-strand breaks (DSBs) are toxic DNA lesions that can be repaired by non-homologous end-joining (NHEJ) or homologous recombination (HR). Mutations in HR genes elicit a predisposition to cancer; yet, they also result in increased sensitivity to certain DNA damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. To optimally implement PARP inhibitor treatment, it is important that patients with HR-deficient tumors are adequately selected.

Areas covered: Herein, the authors describe the HR pathway mechanistically and review the treatment of HR-deficient cancers, with a specific focus on PARP inhibition for BRCA1/2-mutated breast and ovarian cancer. In addition, mechanisms of acquired PARP inhibitor resistance are discussed. Furthermore, combination therapies with PARP inhibitors are reviewed, in the context of both HR-deficient and HR-proficient tumors and methods for proper patient selection are also discussed.

Expert opinion: Currently, only patients with germline or somatic BRCA1/2 mutations are eligible for PARP inhibitor treatment and only a proportion of patients respond. Patients with HR-deficient tumors caused by other (epi)genetic events may also benefit from PARP inhibitor treatment. Ideally, selection of eligible patients for PARP inhibitor treatment include a functional HR read-out, in which cancer cells are interrogated for their ability to perform HR repair and maintain replication fork stability.     

Therapeutic targeting of EGFR in malignant gliomas

Importance of the field: Despite the improved prognosis for many cancer patients, the survival of those with malignant gliomas (MGs) remains dismal. Even with aggressive intervention, including surgery, chemotherapy and radiotherapy, the overall 2-year survival rate is only 25% in the most optimistic series, and 5-year survival rates are consistently in the low single digits. Therefore, it is evident that novel therapeutic paradigms are necessary to overcome the inherent limitations of conventional treatments. EGFR gene overexpression can be found in 40 – 50% of patients with MGs, whereas its expression is very low in normal brain. Therapeutic targeting of EGFR has indicated clinical success in the treatment of MGs.

Areas covered in this review: The purpose of this review is to discuss the current status of several EGFR-targeted therapies in MGs patients and address the efficacy of these drugs as monotherapy or in combination with other drugs and/or treatments. We also emphasize the lessons learned and the future perspectives in the development of EGFR-targeted therapies for MGs.

What the reader will gain: A more comprehensive understanding of the molecular, structural and biological characteristics of EGFR and the mechanisms of action of EGFR-targeted antagonists will most likely contribute to the successful use of strategies of EGFR-targeted therapy in the clinic.

Take home message: Therapeutic targeting of EGFR include anti-EGFR mAbs, small-molecule EGFR tyrosine kinase inhibitors, peptide vaccination therapy and other therapeutic strategies. Each EGFR antagonist has its own advantages and limitations in terms of BBB crossing, ease of delivery, combination therapies and potential toxicity. Therefore, a multiple approach combining different agents that target EGFR signaling at multiple levels seems to have potential as future therapeutics for MGs, once the technical and safety issues unique to each of the approaches are overcome.     

Emerging drugs for the treatment of bone metastasis

Introduction: Bone metastases are virtually incurable resulting in significant disease morbidity, reduced quality of life and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Increased understanding of the pathogenesis of bone disease has led to the discovery and clinical utility of bone-targeted agents other than bisphosphonates and denosumab, currently, the standard of care in this setting.

Areas covered: In this review, we present the recent advances in molecular targeted therapies focusing on therapies that inhibit bone resorption and/or stimulate bone formation and novel anti-tumoral agents that exerts significant effects on skeletal metastases, nowadays available in clinical practice or in phase of development.

Expert opinion: New emergent bone target therapies radium-223, mTOR inhibitors, anti-androgens have demonstrated the ability to increase overall survival in bone metastatic patients, other compounds, such as ET-1 and SRC inhibitors, up to now failed to clearly confirm in clinical trials their promising preclinical data.     

Novel molecular targets for the therapy of urothelial carcinoma

Introduction: First-line platinum-based combinations are active in locally advanced and metastatic urothelial carcinoma; however, long-term outcomes including disease-specific and overall survival remain suboptimal. In addition, approximately 40 – 50% of patients with advanced urothelial carcinoma have coexisting medical issues that preclude the use of cisplatin-based therapy. Improvements in our understanding of the molecular mechanisms of urothelial tumorigenesis have led to first-generation clinical trials evaluating novel agents targeting molecular pathways. These are particularly relevant in regard to subpopulations. Novel trial designs warrant consideration to accelerate accrual.

Areas covered: In this review, novel molecular targets for the therapy of urothelial carcinoma, as well as recently completed and ongoing clinical trials utilizing novel targeted agents, are discussed. A Medline search with key words, abstracts reported at national conferences on urothelial carcinoma and NCI clinical trial identifiers was used for this review.

Expert opinion: Improved understanding of molecular biology has identified a number of new molecular targets, but there is a seeming absence of one dominant molecular driver for urothelial cancer. An adaptive and biomarker-derived strategy may be warranted. Clinical trials utilizing targeted agents are ongoing and results are awaited.     

Towards a targeted multi-drug delivery approach to improve therapeutic efficacy in breast cancer

Importance of the field: Significant improvements in breast cancer treatments have resulted in a significant decrease in mortality. However, current breast cancer therapies, for example, chemotherapy, often result in high toxicity and nonspecific side effects. Other treatments, such as hormonal and antiangiogenic therapies, often have low treatment efficacy if used alone. In addition, acquired drug resistance decreases further the treatment efficacy of these therapies. Intra-tumor heterogeneity of the tumor tissue may be a major reason for the low treatment efficacy and the development of chemoresistance. Therefore, targeted multi-drug therapy is a valuable option for addressing the multiple mechanisms that may be responsible for reduced efficacy of current therapies.

Areas covered in this review: In this article, different classes of drugs for treating breast cancer, the possible reasons for the drug resistance in breast cancer, as well as different targeted drug delivery systems are summarized. The current targeting strategies used in cancer treatment are discussed.

What the reader will gain: This article considers the current state of breast cancer therapy and the possible future directions in targeted multi-drug delivery for treating breast cancer.

Take home message: A better understanding of tumor biology and physiological responses to nanoparticles, as well as advanced nanoparticle design, are needed to improve the therapeutic outcomes for treating breast cancer using nanoparticle-based targeted drug delivery systems. Moreover, selective delivery of multi-drugs to tumor tissue using targeted drug delivery systems may reduce systemic toxicity further, overcome drug resistances, and improve therapeutic efficacy in treating breast cancer.