Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 12, Issue 2, 2012

The past few decades have witnessed remarkable changes in the management of patients with cancer. Although more patients than ever before are being diagnosed with cancer, the survival rate for patients with cancer has increased substantially [1]. The refined use of surgical strategies, conventional cytotoxic agents, and radiotherapy and the development of targeted agents have been integral components of this success across the different malignancies. However, with increased survival came the emergence of skeletal complications (that had previously been common mostly in the last few months of life for patients with cancer [eg, hypercalcemia of malignancy and fractures]) in patients with life expectancies of several months to years. Advances in supportive care have offered improved pain management, more effective antiemetic and antidiarrheal medications [2,3], refined palliative radiotherapeutic strategies (including bone-seeking radionuclides) [4], and the application of bisphosphonate therapy to prevent cancer treatment-induced bone loss and reduce the risk of skeletal-related events from bone metastases [5]. In the past 2 years, with the emergence of evidence that, in addition to their established supportive care roles, bisphosphonates appear to also possess clinically meaningful anticancer activity, the fields of anticancer therapy and supportive care have partially merged. In this Hot Topics edition of Anticancer Agents in Medicinal Chemistry, the clinical development of bisphosphonates in the oncology setting is reviewed in detail (Widler et al., p. X), and the emerging anticancer data for this class of agents are discussed (Clézardin, p. X). Recent data releases from database analyses and ongoing trials of bisphosphonates have demonstrated their potential to provide benefits beyond supportive care. These potential benefits are especially robust in the early disease setting—and may even extend to cancer prevention (Chlebowski and Col, p X.). The manuscripts in this edition therefore review the rationale for the elevation of bisphosphonates from adjunctive palliative agents to anticancer therapies in their own right. Early evidence for this in advanced cancer settings first emerged with zoledronic acid in the genitourinary cancers (as reviewed by Saad and Mulders, p. X), as well as in lung cancer and solid tumors other than breast and prostate cancer (as reviewed in my manuscript, p. X). However, the potential for clinical anticancer effects with the other bisphosphonates in patients with metastatic disease is unknown. It is likely that differences between bisphosphonates will come to light as further trial data emerge. Most recently, Morgan et al., [6] reported that zoledronic acid is superior to clodronate not only for the prevention of skeletal-related events but also for improving overall and progression-free survival in patients with newly diagnosed multiple myeloma (as reviewed by Terpos, p. X). Further information is expected from ongoing comparative trials, especially in the early breast cancer setting, wherein zoledronic acid has already demonstrated benefits beyond those achievable with endocrine therapy alone in randomized controlled trials (as reviewed by Gnant, p. X). The role of bisphosphonates and the choice of which agent to utilize in each of the oncology settings is expected to evolve as data from the ongoing studies mature. However, given the wealth of clinical experience with these agents and their favorable overall tolerability profile of these agents, the anticancer potential of bisphosphonate therapy is likely to remain a hot topic in the next few years....

In the early 1960s, inorganic pyrophosphate (PPi) was found to be present in body fluids and to act as a natural inhibitor of calcification by its interaction with hydroxyapatite. In addition to inhibiting the formation of calcium phosphate, PPi also inhibited dissolution of hydroxyapatite crystals, which made it interesting for pharmacologic applications in the treatment of diseases associated with excessive bone resorption. However, PPi is metabolically unstable because of rapid hydrolysis of the P-O-P backbone by hydrolytic enzymes in the gastrointestinal tract. In the search for more stable analogues of PPi, attention turned to the chemical class of bisphosphonates (BPs). The first BPs were synthesized in the 19th century and widely used for industrial applications. Bisphosphonates are formally derived from PPi by replacement of the bridging oxygen atom by a carbon atom, resulting in a P-C-P moiety that is resistant to hydrolysis. In addition to its decisive role in stability, the central carbon atom also provides an attachment point for 2 additional substituents (R1 and R2). While R1 is preferentially a hydroxy group, allowing such derivatives to act as powerful tridentate ligands for calcium (bone hook), R2 is mainly responsible for antiresorptive potency. The clinically available BPs can be divided into 2 subclasses based on their structure and molecular mechanism of action. The simple, non-nitrogen-containing derivatives can be incorporated into non-hydrolyzable cytotoxic ATP analogues. The more potent nitrogen-containing BPs inhibit FPPS, a key enzyme in the mevalonate pathway. Details of this crucial molecular interaction have recently been elucidated. Members of this class have a wide therapeutic window between therapeutic inhibition of bone resorption and undesired inhibition of bone formation, and several have found widespread use for the treatment of benign and malignant bone disease.

Bone is a common site of metastasis from advanced cancers, and metastasis to bone accounts for the majority of distant recurrences from breast and prostate cancers. Bone metastases are characterized by increased rates of bone turnover. Bisphosphonates are extensively used in the treatment of metastatic bone disease to reduce the rates of osteolysis and the risk of skeletal-related events. In addition, bisphosphonates have demonstrated direct and indirect anticancer potential in preclinical studies. These activities include induction of apoptosis, inhibition of invasion, synergistic cytotoxicity with chemotherapy agents, antiangiogenic properties, and modulation of immunologic activity against transformed cells. Notably, these activities of bisphosphonates are not limited to the bone microenvironment; indeed some effects are mediated on the cancer cells themselves. These preclinical data provide the rationale for the underlying potential clinical benefits from bisphosphonates (e.g., prevention of metastasis to bone and other sites in the early breast cancer setting and delayed disease progression in malignancies involving colonization of bone [e.g., multiple myeloma]). This review article summarizes the preclinical anticancer activities of bisphosphonates in various cancer types and evaluates their potential contributions to the recently demonstrated clinical effects.

Despite progress in surgical and adjuvant therapy, a subset of patients with early stage breast cancer experience disease recurrence and/or distant metastases. Disseminated tumor cells (DTCs) in the bone marrow are believed to be the source of late relapses in bone and other tissues. Bone is the most common site of breast cancer metastasis, and agents that modify the bone microenvironment could therefore affect the disease course. Bisphosphonates are an effective bone-targeted therapeutic option for preventing cancer treatment- induced bone loss (CTIBL) in pre- and postmenopausal women with breast cancer. Bisphosphonates inhibit osteoclast-mediated bone resorption, thereby inhibiting the release of growth factors necessary to promote cancer cell growth, differentiation, and tumor formation in bone. Preclinical and clinical data also suggest anticancer synergy between cytotoxic chemotherapy agents and bisphosphonates. Recent trials of zoledronic acid in the adjuvant setting in breast cancer have demonstrated reduced disease recurrence in bone and other sites. Currently, several ongoing clinical trials are evaluating whether antiresorptives can inhibit disease recurrence and the development of bone metastases from breast cancer. Based on recent data, the role of bisphosphonates in the breast cancer setting is expected to expand in the future. With recent changes to treatment guidelines, routine use of bisphosphonates to prevent bone loss during adjuvant therapy is likely to become standard practice, especially for patients receiving endocrine therapy. Furthermore, the use of zoledronic acid to reduce the risk of recurrence is emerging based on ongoing clinical research.

Bisphosphonates inhibit osteoclast-mediated bone resorption and have been used extensively to prevent skeletal-related events in patients with bone lesions from multiple myeloma (MM). In addition, in vitro and in vivo preclinical data suggest that bisphosphonates also have antimyeloma properties that may induce myeloma cell apoptosis, activate an anticancer immune response, inhibit angiogenesis, and reduce tumor burden, supporting an expanded role for bisphosphonates. Signals for improved survival in the clinic first emerged in retrospective analyses of MM patient subgroups in larger clinical trials. Recently, improved progression-free survival and overall survival with bisphosphonates have been reported in the overall populations of large-scale randomized clinical trials. Several ongoing clinical trials will help further define the role of bisphosphonates during antimyeloma therapy. Overall, bisphosphonates appear to be well tolerated in patients with MM; the most common adverse events are mild and can be easily managed. However, emphasis on renal monitoring and preventive dentistry are necessary to reduce the risk of potential adverse events, and have become the standard of care for patients with MM.

Anticancer therapies have traditionally been targeted directly against cancer cell growth. However, newer treatment strategies also target the microenvironment that supports metastatic cancer cell growth. Bisphosphonates are the standard of care for maintaining bone health in patients with bone metastases from solid tumors and bone lesions from multiple myeloma, and emerging evidence supports potential anticancer activity of bisphosphonates. Zoledronic acid (ZOL), a third-generation nitrogen-containing bisphosphonate, is currently advised for reducing the risk of skeletal morbidity in patients with bone metastases from prostate cancer and other genitourinary cancers, such as renal cell carcinoma and bladder cancer. Clinical studies indicate that ZOL can normalize bone marker levels (a potential measure of skeletal disease burden), which may improve survival in patients with aggressive bone disease from prostate and other genitourinary cancers, supporting a broader therapeutic role for ZOL in genitourinary malignancies. This review examines the rationale and emerging evidence supporting the anticancer activity of bisphosphonates, especially ZOL, against prostate and other genitourinary cancers.

Bisphosphonates are the current standard of care for patients with bone metastases from advanced solid tumors. Zoledronic acid has demonstrated the broadest activity in this setting, and is approved for the prevention of skeletal-related events from bone metastases from a variety of solid tumors in addition to breast cancer and multiple myeloma. Ongoing studies are evaluating the antiresorptive potentials of investigational agents in these settings. A large body of preclinical evidence and recent clinical developments support the hypothesis that zoledronic acid can exert clinically meaningful anticancer activities in some settings, thereby improving disease outcomes and survival. These data are especially strong in breast cancer and multiple myeloma, and are emerging in other cancer settings. This review article will discuss the emerging data suggesting an anticancer role for bisphosphonates in the context of lung cancer and solid tumors other than breast and genitourinary malignancies.

Bisphosphonates are commonly used in patients with breast cancer to reduce skeletal-related events in metastatic disease and to mitigate bone loss associated with cancer therapy in early stage disease. In addition, adjuvant breast cancer trials evaluating the oral bisphosphonate clodronate suggested a reduction in cancer recurrence, but the findings were mixed, with 2 positive and 1 negative report. In the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 study, adding the intravenous bisphosphonate zoledronic acid to endocrine therapy in premenopausal breast cancer patients significantly prolonged disease-free survival versus endocrine therapy alone (hazard ratio = 0.68; p = 0.008) at 62 months, and reduced local, regional, and distant recurrences. Clinical trial findings from other adjuvant trials (Z-FAST, ZO-FAST), neoadjuvant studies, and studies involving disseminated tumor cells (DTCs) are generally supportive of the ABCSG-12 conclusion, and recent data from AZURE suggest the importance of menopausal status. Preclinical studies provide data on the mechanisms of action that could mediate bisphosphonate direct and indirect anti-cancer effects. Recently, several observational studies (2 cohort studies and 2 case-control analyses) have associated oral bisphosphonate use with a lower breast cancer incidence. Such reports require cautious interpretation because confounding by indication is an issue: bisphosphonates are prescribed for women with low bone mineral density, and women with low bone density are at decreased breast cancer risk.

Lapatinib, a dual EGFR/HER2 kinase inhibitor, is approved for use in patients with trastuzumab-refractory HER2- overexpressing breast cancer. Increased PI3K signaling has been associated with resistance to trastuzumab, although its role in lapatinib resistance remains unclear. The purpose of the current study was to determine if PI3K/mTOR activity affects lapatinib sensitivity. Reduced sensitivity to lapatinib was associated with an inability of lapatinib to inhibit Akt and p70S6K phosphorylation. Transfection of constitutively active Akt reduced lapatinib sensitivity, while kinase-dead Akt increased sensitivity. Knockdown of 4EBP1 also increased lapatinib sensitivity, in contrast to p70S6K knockdown, which did not affect response to lapatinib. Pharmacologic inhibition of mTOR using rapamycin or ridaforolimus increased lapatinib sensitivity and reduced phospho-Akt levels in cells that showed poor response to single-agent lapatinib, including those transfected with hyperactive Akt. Finally, combination mTOR inhibition plus lapatinib resulted in synergistic inhibition of proliferation, reduced anchorage-independent growth, and reduced in vivo tumor growth of HER2- overexpressing breast cancer cells that have primary trastuzumab resistance. Our data suggest that PI3K/mTOR inhibition is critical for achieving optimal response to lapatinib. Collectively, these experiments support evaluation of lapatinib in combination with pharmacologic mTOR inhibition as a potential strategy for inhibiting growth of HER2-overexpressing breast cancers that show resistance to trastuzumab and poor response to lapatinib.

KRAS and BRAF mutations lead to the constitutive activation of EGFR signaling through the oncogenic Ras/Raf/Mek/Erk pathway. Currently, KRAS is the only potential biomarker for predicting the efficacy of anti-EGFR monoclonal antibodies (mAb) in colorectal cancer (CRC). However, a recent report suggested that the use of cetuximab was associated with survival benefit among patients with p.G13D-mutated tumors. Furthermore, although the presence of mutated BRAF is one of the most powerful prognostic factors for advanced and recurrent CRC, it remains unknown whether patients with BRAF-mutated tumors experience a survival benefit from treatment with anti-EGFR mAb. Thus, the prognostic or predictive relevance of the KRAS and BRAF genotype in CRC remains controversial despite several investigations. Routine KRAS/BRAF screening of pathological specimens is required to promote the appropriate clinical use of anti-EGFR mAb and to determine malignant phenotypes in CRC. The significance of KRAS/BRAF mutations as predictive or prognostic biomarkers should be taken into consideration when selecting a KRAS/BRAF screening assay. This article will review the spectrum of KRAS/BRAF genotype and the impact of KRAS/BRAF mutations on the clinicopathological features and prognosis of patients with CRC, particularly when differentiating between the mutations at KRAS codons 12 and 13. Furthermore, the predictive role of KRAS/BRAF mutations in treatments with anti-EGFR mAb will be verified, focusing on KRAS p.G13D and BRAF mutations.

Procathepsin D (pCD) is overexpressed and secreted by cells of various tumor types including breast and lung carcinomas, affecting multiple features of tumor cells including proliferation, invasion, metastasis and apoptosis. As more and more attention has been focused on potential use of pCD in clinical practice, we devoted this paper to summarize the three major potentials of pCD—tumor marker, potential drug and screening agent. Despite more than 20 years of studies and numerous reports of the association between pCD level and tumor size, tumor grade, tumor aggressiveness, and incidence of metastasis, pCD is still not used as a marker of cancer development. This is due to problems in distinguishing between pCD expressed by cancer derived cells and normal tissue cells and in the exact measuring of its different molecular forms (pCD, single chain cathepsin D (CD) and two chain CD) in tumor tissue. Numerous studies demonstrated that pCD secreted from cancer cells affects multiple stages of tumor progression. Subsequent data showing that inhibition of pCD secretion from cancer cells can inhibit cancer cell growth in vitro and in vivo suggested the possibility of using pCD suppression in clinical practice. A third possibility of using pCD in clinical practice is represented by the use of anti-pCD autoantibodies in screening cancer patients or in correlation with the level of these antibodies with the progress of cancer disease. Despite the fact that preliminary findings suggested such correlation, more detailed studies revealed significant setbacks.