S. Percy Ivy

Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways.

Tumor relapse and metastasis remain major obstacles for improving overall cancer survival, which may be due at least in part to the existence of cancer stem cells (CSCs). CSCs are characterized by tumorigenic properties and the ability to self-renew, form differentiated progeny, and develop resistance to therapy. CSCs use many of the same signaling pathways that are found in normal stem cells, such as Wnt, Notch, and Hedgehog (Hh). The origin of CSCs is not fully understood, but data suggest that they originate from normal stem or progenitor cells, or possibly other cancer cells. Therapeutic targeting of both CSCs and bulk tumor populations may provide a strategy to suppress tumor regrowth. Development of agents that target critical steps in the Wnt, Notch, and Hh pathways will be complicated by signaling cross-talk. The role that embryonic signaling pathways play in the function of CSCs, the development of new anti-CSC therapeutic agents, and the complexity of potential CSC signaling cross-talk are described in this Review.

Heat shock protein 90.

Purpose of review Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signaling proteins, as well as multiple mutated, chimeric, or overexpressed signaling proteins, which promote cancer cell growth or survival or both. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the inactivation, destabilization, and eventual degradation of Hsp90 client proteins, and they have shown promising antitumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, has completed Phase I clinical trial, and several Phase II trials are in progress. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival. Recent findings Recently identified clients of Hsp90 participate, frequently in overlapping pathways, in mediating cancer cell survival. These include Akt, Her2, and HIF-1&agr;. Thus, by inhibiting multiple survival pathways used by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Furthermore, Hsp90 modulates androgen receptor activity and the activity of several mutated kinases characteristic of several leukemias and lymphomas, making Hsp90 inhibition an attractive modality in these cases. Summary Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should augment the treatment of multiple forms of cancer.

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents.

Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study

BACKGROUND Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. METHODS In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. FINDINGS Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). INTERPRETATION Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. FUNDING American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.

An overview of small-molecule inhibitors of VEGFR signaling

VEGFR inhibitors are in broad use for the treatment of metastatic renal-cell carcinoma, gastrointestinal stromal tumors and hepatocellular carcinoma and in development in a number of other oncology indications, including colorectal cancer, non-small-cell lung cancer, pancreatic cancer, thyroid malignancies, ovarian cancer, breast cancer and sarcomas. This Review outlines the structure–activity relationships of the 44 VEGFR inhibitors currently in development. An overview of the pharmacokinetic profile of each molecule and its stage in development is provided. Phase III clinical trials being conducted for licensing of these agents for specific indications and phase III developmental efficacy trials are described in detailed tables that include the disease studied, trial design including combination therapy, study end points, and projected or final accrual. The relative frequency of on-target and off-target adverse events observed in 3,060 patients is described for a subset of agents in development in clinical trials sponsored by the National Cancer Institute. No interagent comparisons were undertaken and no data from pharmaceutical pharmacovigilance databases were used. The on-target effects seem to be mechanistically based and predicted by VEGFR inhibition. Small-molecule inhibitors of angiogenesis are active in a wide variety of malignancies and fill a unique niche for cancer therapeutics.

Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation

Significance This study demonstrates that antiangiogenic therapy increases tumor blood perfusion in a subset of newly diagnosed glioblastoma patients, and that it is these patients who survive longer when this expensive and potentially toxic therapy is combined with standard radiation and chemotherapy. This study provides fresh insights into the selection of glioblastoma patients most likely to benefit from antiangiogenic treatments. Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of nGBM response to cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, using MRI techniques and blood biomarkers in prospective phase II clinical trials of cediranib with chemoradiation vs. chemoradiation alone in nGBM patients. We demonstrate that improved perfusion occurs only in a subset of patients in cediranib-containing regimens, and is associated with improved overall survival in these nGBM patients. Moreover, an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers, such as changes in plasma placenta growth factor and sVEGFR2. Finally, treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy. In conclusion, tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic form of therapy, and these results may provide new insight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments.

Phase I Pharmacokinetic-Pharmacodynamic Study of 17-(Allylamino)-17-Demethoxygeldanamycin (17AAG, NSC 330507), a Novel Inhibitor of Heat Shock Protein 90, in Patients with Refractory Advanced Cancers

Purpose: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), a benzoquinone antibiotic, down-regulates oncoproteins by binding specifically to heat shock protein 90 (HSP90). We did a phase I study of 17AAG to establish the dose-limiting toxicity and maximum tolerated dose and to characterize 17AAG pharmacokinetics and pharmacodynamics. Experimental Design: Escalating doses of 17AAG were given i.v. over 1 or 2 hours on a weekly × 3 schedule every 4 weeks to cohorts of three to six patients. Plasma pharmacokinetics of 17AAG and 17-(amino)-17-demethoxygeldanamycin (17AG) were assessed by high-performance liquid chromatography. Expression of HSP70 and HSP90 in peripheral blood mononuclear cells was measured by Western blot. Results: Forty-five patients were enrolled to 11 dose levels between 10 and 395 mg/m2. The maximum tolerated dose was 295 mg/m2. Dose-limiting toxicity occurred in both patients (grade 3 pancreatitis and grade 3 fatigue) treated with 395 mg/m2. Common drug-related toxicities (grade 1 and 2) were fatigue, anorexia, diarrhea, nausea, and vomiting. Reversible elevations of liver enzymes occurred in 29.5% of patients. Hematologic toxicity was minimal. No objective responses were observed. 17AAG pharmacokinetics was linear. Peak plasma concentration and area under the curve of 17AG, the active major metabolite of 17AAG, increased with 17AAG dose, but the relationships were more variable than with 17AAG. 17AAG and 17AG in plasma were >90% protein bound. There were no consistent changes in peripheral blood mononuclear cell HSP90 or HSP70 content. Conclusions: 17AAG doses between 10 and 295 mg/m2 are well tolerated. 17AAG pharmacokinetics is linear. Peripheral blood mononuclear cell HSP90 and HSP70 are uninformative pharmacodynamic markers. The dose recommended for future studies is 295 mg/m2 weekly × 3, repeated every 4 weeks.

Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Advanced Cancer

Purpose: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules. Experimental Design: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m2 daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily × 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies. Results: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m2 on the daily × 5 schedule; 112 mg/m2 on the daily × 3 schedule; and 220 mg/m2 on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily × 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies. Conclusion: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.

A Phase II Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Hormone-Refractory Metastatic Prostate Cancer

Purpose: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with antiproliferative activity in several mouse xenograft models, including prostate cancer models. A two-stage phase II study was conducted to assess the activity and toxicity profile of 17-AAG administered to patients with metastatic, hormone-refractory prostate cancer. Experimental Design: Patients with at least one prior systemic therapy and a rising prostate-specific antigen (PSA) were eligible. Patients received 17-AAG at a dose of 300 mg/m2 i.v. weekly for 3 of 4 weeks. The primary objective was to assess the PSA response. Secondary objectives were to determine overall survival, to assess toxicity, and to measure interleukin-6, interleukin-8, and maspin levels and quality of life. Results: Fifteen eligible patients were enrolled. The median age was 68 years and the median PSA was 261 ng/mL. Patients received 17-AAG for a median number of two cycles. Severe adverse events included grade 3 fatigue (four patients), grade 3 lymphopenia (two patients), and grade 3 back pain (two patients). The median PSA progression-free survival was 1.8 months (95% confidence interval, 1.3-3.4 months). The 6-month overall survival was 71% (95% confidence interval, 52-100%). Conclusions: 17-AAG did not show any activity with regard to PSA response. Due to insufficient PSA response, enrollment was stopped at the end of first stage per study design. The most significant severe toxicity was grade 3 fatigue. Further evaluation of 17-AAG at a dose of 300 mg/m2 i.v. weekly as a single agent in patients with metastatic, hormone-refractory prostate cancer who received at least one prior systemic therapy is not warranted.

Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition

Induction of epithelial-to-mesenchymal transition (EMT) in cancer stem cells (CSCs) can occur as the result of embryonic pathway signaling. Activation of Hedgehog (Hh), Wnt, Notch, or transforming growth factor-β leads to the upregulation of a group of transcriptional factors that drive EMT. This process leads to the transformation of adhesive, non-mobile, epithelial-like tumor cells into cells with a mobile, invasive phenotype. CSCs and the EMT process are currently being investigated for the role they play in driving metastatic tumor formation in breast cancer. Both are very closely associated with embryonic signaling pathways that stimulate self-renewal properties of CSCs and EMT-inducing transcription factors. Understanding these mechanisms and embryonic signaling pathways may lead to new opportunities for developing therapeutic agents to help prevent metastasis in breast cancer. In this review, we examine embryonic signaling pathways, CSCs, and factors affecting EMT.