Current Cancer Drug Targets - Volume 11, Issue 6, 2011

Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells (e.g. with traditional chemotherapy). Targeted cancer therapies may be more effective than current treatments and less harmful to normal cells. The main categories of targeted therapy are small molecules and monoclonal antibodies. Many oncologists believe that targeted therapies are the chemotherapy of the future. As solid tumor cancer continues to be viewed as a chronic condition, methods for long-term treatment, with less side-effects, continue to be investigated. In this special issue current status of molecular targeted therapy for gastrointestinal cancer will be discussed. Molecular Targeted Therapy for Colorectal Cancer Colorectal cancer (CRC) remains the third most common malignancy and the third leading cause of cancer death worldwide. Approximately 25% present with metastases as initial diagnosis and almost 50% of patients with CRC will develop metastases, contributing to the high mortality rates reported for CRC. The backbone of first-line palliative chemotherapy consists of a fluoropyrimidine [intravenous 5-fluorouracil (5-FU) or oral fluoropyrimidines capacitabine (CAP) and uracilftorafur (UFT)] in various combinations and schedules. Combination chemotherapy with 5-FU/LV (leucovorin)/oxaliplatin (FOLFOX) or 5-FU/LV/irinotecan (FOLFIRI) provides higher response rates (RR), longer progression-free survival (PFS) and better overal survival (OS) [1]. The exposure to all three cytotoxics (fluoropyrimidines, oxaliplatin and irinotecan) in various sequences results in the longest survival [2]. The introduction of monoclonal antibodies (mAb) against vascular endothelial growth factor (VEGF) and against the epidermal growth factor receptor (EGFR) into the treatment protocols for advanced CRC has significantly improved the outcomes with median survival now reaching almost 24 months (for review see [3-5]). Adoption of hepatic resection, especially after induction chemotherapy, even in patients with advanced liver metastases has prolonged median survival further up to 29 months [6, 7]. Bevacizumab (BEV, Avastin™), a recombinant, humanized IgG1 mAb against all isoforms of VEGF-A, increases OS, PFS and RR in first-line treatment in combination with 5-FU/LV/irinotecan and in combination with 5-FU/LV or CAP alone. According to a recently presented Greek phase III study XELIRI (CAP/irinotecan)-BEV did not show significant differences in efficacy as compared to FOLFIRI-BEV (median PFS 14.6 mo. vs. 15.8 mo.; median OS 20.0 mo. vs. 26.2 mo.)1. However, the toxicity profile was different (less neutropenia and metabolic disorders but more diarrhea and vomiting with XELIRIBEV). In combination with FOLFOX/XELOX BEV improves PFS in first-line treatment [8] but not OS and RR. However, improvement in PFS, OS and RR has been shown with FOLFOX-BEV in second-line treatment of metastatic CRC [9] (Table 1, for meta-analysis see [10]). The addition of mitomycin to CAP + BEV did not show extra benefit [11]. Other long-term observational cohort studies, such as first BEAT [12] and BRITE [13], have now confirmed BEV study data. Specific class related side-effects of BEV are: hypertension, proteinuria, arterial thrombosis, mucosal bleeding, gastrointestinal perforation and wound healing problems. There are no validated predictive molecular markers available for BEV [14]. In medically fit older patients, BEV provides similar PFS and OS benefits as in younger patients [15]. Downstaging of isolated liver metastases is another interesting aspect currently investigated in the phase II BOXER study (CAPOX + BEV) and phase III CELIM 2 study (FOLFOXIRI ± BEV). In the first study, overall RR was 78% (95% confidence interval 63% to 89%), conversion rate of primary unresectable metastases was 40% (12/30), and primary resection rate was 49% (22/45) [16]. Results of the second study are still pending. Efficacy of FOLFOXIRI-BEV combination is also currently investigated by the Italian GONO group in the TRIBE study (Table 1). One issue that is still debated is length of treatment in the palliative situation. The OPTIMOX1 study has shown that after six cycles of FOLFOX, oxaliplatin may be safely stopped while continuing 5-FU/LV for a further 12 cycles after which oxaliplatin is reintroduced again, without compromising efficacy [17].In contrast, complete discontinuation of chemotherapy had a negative impact on duration of disease control and PFS compared with the maintenance therapy strategy as has been shown in the OPTIMOX2 study [18]. Other studies, such as MRC CRO 6B [19], GISCAD [20], and MRC COIN (Adams T., ESMO 2009) showed only a slight reduction of OS while improving quality of life with intermittent treatment. The MARCO trial tried to answer the question whether BEV alone can be used as maintenance therapy following induction with XELOX-BEV2. As a result, BEV was not inferior to continuation XELOX-BEV (median PFS 10.3 mo. vs. 11.0 mo.; median OS 20.7 mo. vs. 25.3 mo.). The Dutch CAIRO3 study is currently investigating CAP-BEV maintenance therapy in comparison to observation following induction with 6 cycles CAPOX-BEV. The German AIO group investigates CAP-BEV or BEV maintenance therapy in comparison to observation following induction with XELOX/CAPOX/FOLFOX (AIO Trial KRK 0207). Currently, the label of BEV in colorectal cancer prescribes to continue the administration until disease progression (or unacceptable toxicity). Adjuvant treatment is recommended for stage III and “high risk” (lymph nodes sampling < 12; poorly differentiated tumor; vascular or lymphatic or perineural invasion; tumor presentation with obstruction or tumor perforation and pT4 stage) stage II CRC patients. Large prospective adjuvant phase III studies, such as MOSAIC [21, 22], NSABP C-07 [23], X-ACT [24] and NO16968/XELOXA [25] have established FLOX/FOLFOX/XELOX as standard treatment and 5-FU/LV or CAP when oxaliplatin is contraindicated. In contrast, there was no benefit for CPT-11 (irinotecan) based regimens according to the results of CALGB 89803 [26], PETACC-3 [27] and Accord02 [28] studies. Unfortunately, the addition of BEV to mFOLFOX6 does not significantly prolong disease-free survival (DFS) in stages II and III colon cancer, the primary endpoint of the large phase III NSABP C-08 study [29]. In the AVANT study, BEV did not prolong DFS or OS when added to either FOLFOX4 or XELOX in patients with stage III colon cancer3. Given this lack of improvement in DFS and OS, the use of BEV cannot be recommended in the adjuvant treatment of patients with CRC. Results of other studies, such as QUASAR 2 (CAP ± BEV) and ECOG E5202 (FOLFOX ± BEV) are still pending.....

Although combination chemotherapy has been shown to be more effective than single agents in advanced esophagogastric cancer, the better response rates have not fulfilled their promise as overall survival times from best combination still range between 8 to 11 months. So far, the development of targeted therapies stays somewhat behind their integration into treatment concepts compared to other gastrointestinal diseases. Thus, the review summarizes the recent advances in the development of targeted therapies in advanced esophagogastric cancer. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors EGFR1 and HER2. For trastuzumab and bevacizumab, phase III trial results have been presented recently. While addition of trastuzumab to cisplatin/5-fluoropyrimidine-based chemotherapy results in a clinically relevant and statistically significant survival benefit in HER 2+ patients, the benefit of the addition of bevacizumab to chemotherapy was not significant. Thus, all patients with metastatic disease should be tested for HER-2 status in the tumor. Trastuzumab in combination with cisplatin/5-fluoropyrimidine-based chemotherapy is the new standard of care for patients with HER2-positive advanced gastric cancer.

Gastrointestinal stromal tumors (GIST) are mesenchymal tumors that occur predominantly in the stomach and the small bowel. Their pathogenesis is generally based on primary activating mutations in the KIT or PDGFRα genes that result in constitutive activation of receptor tyrosine kinase activity. Imatinib, first designed to competitively inhibit the ATP-binding pocket of the BCR-ABL tyrosine kinase exhibits inhibition also in the KIT and PDGFRα tyrosine kinases, which revolutionized the therapy of gastrointestinal stromal tumors, a disease without any systemic treatment options prior to imatinib. Clinical benefit is achieved in approximately 85% of patients with unresectable or metastatic disease with a median progression-free survival of 19 to 26 months and an overall survival approaching 5 years. Disease progression results from different mechanisms of resistance most frequently involving the emergence of secondary mutations in KIT exons 13, 14, or 17. Several newer drugs have been studied in patients failing or being intolerant to imatinib, including the multitargeted agent sunitinib as well as other KIT targeting tyrosine kinase inhibitors like nilotinib or agents targeting alternative pathways like anti-angiogenic agents, mTOR-, RAF kinase- and chaperone inhibitors.

Despite remarkable progress that has been made in the recent years in the treatment of gastrointestinal tumors, in particular colorectal cancer, the prognosis of pancreatic cancer remains dismal. Five years after diagnosis almost all patients have died. At early stages of the disease surgery is the only modality to achieve long term survival. In the palliative setting gemcitabine confers some benefit to patients with advanced pancreatic cancer. A large number of chemotherapy combinations has been tested in patients with advanced pancreatic cancer. Only one combination showed significant improvement of survival, however also increased toxicity. The introduction of targeted therapies raised hopes for a better treatment of pancreatic cancer. However, most of the compounds tested so far failed to improve the survival of patients with pancreatic cancer. This review summarizes molecular targets examined so far in pancreatic cancer including matrix metalloproteinase inhibitors, farnesyltransferase inhibitors, vascular endothelial growth factor and epidermal growth factor receptor inhibitors and points out novel promising strategies for this difficult-to-treat tumor.

Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis and worldwide rising incidence during the last years. Although orthotopic liver transplantation, surgical resection and local destruction (alcohol or acetic acid and thermal ablation) are the only curative approaches, this can be accomplished in a minority of patients, since most of them present with advanced disease. In addition, those patients who have undergone curative treatment experience a high tumor recurrence rate. Non-resectable HCC is associated with a poor prognosis due to wide resistance to chemotherapeutic agents. It is therefore essential to search for new therapeutical approaches. After several years of preclinical research, the first clinical study data on molecular targeting therapy are now available for this tumor entity. Inhibitors of the epidermal growth factor receptor (EGFR) family, such as erlotinib and lapatinib were recently investigated. Furthermore, bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), sunitinib, a multiple kinase inhibitor that blocks several receptor tyrosine kinases, and sorafenib (BAY 43-9006), a multiple kinase inhibitor that blocks not only receptor tyrosine kinases but also serine/threonine kinases along the RAS/RAF/MEK/ERK pathway, were studied, as well. Until now, the only agent that has to be proven to be effective in terms of survival outcome in two phase III placebo-controlled studies is sorafenib, which became the current standard for palliative treatment.

Recent studies describe a heterogeneous population of cells of the myeloid lineage, termed myeloid derived suppressor cells (MDSC), which are observed with increased prevalence in the peripheral blood and tumor microenvironment of cancer patients, including pancreatic cancer. Accumulation of MDSC in the peripheral circulation has been related to extent of disease, and correlates with stage. MDSC have primarily been implicated in promoting tumor growth by suppressing antitumor immunity. There is also compelling evidence MDSC are also involved in angiogenesis and metastatic spread. Two main subsets of MDSC have been identified in cancer patients: a monocytic subset, characterized by expression of CD14, and a granulocytic subset characterized by expression of CD15. Both subsets of MDSC actively suppress host immunity through a variety of mechanisms including production of reactive oxygen species and arginase. Just as in humans, accumulation of monocytic and granulocytic MDSC has been noted in the bone marrow, spleen, peripheral circulation, and tumors of tumor bearing mice. Successful targeting of MDSC in mice is associated with improved immune responses, delayed tumor growth, improved survival, and increased efficacy of vaccine therapy. By further elucidating mechanisms of MDSC recruitment and maintenance in the tumor environment, strategies could be developed to reverse immune tolerance to tumor. We discuss here what is currently known about MDSC as well as some potential strategies targeting MDSC in the context of our work on pancreatic cancer and recent literature. Due to the number of new reports on MDSC, the most pertinent ones have been selected.

The polyisoprenylation pathway incorporates a reversible step that metabolizes polyisoprenylated methylated proteins from the ester to the carboxylate form. Polyisoprenylated protein methyl transferase (PPMTase) catalyses the esterification whereas polyisoprenylated methylated protein methyl esterase (PMPMEase) hydrolyzes them. Significant changes in the balance between the two enzymes may alter polyisoprenylated protein function possibly resulting in disease. Previous studies show that PMPMEase is the serine hydrolase, Sus scrofa carboxylesterase. Its susceptibility to the nonspecific serine hydrolase inhibitor, phenylmethylsulfonyl fluoride (PMSF) paved the way for its use as a prototypical compound to design and synthesize a series of putative high affinity specific inhibitors of PMPMEase. Pseudo first-order kinetics revealed an over 680-fold increase in kobs/[I] values from PMSF (6 M-1s-1), S-phenyl (L-50, 180 M-1s-1), S-benzyl (L-51, 350 M-1s-1), S-trans, trans-farnesyl (L-28, 2000 M-1s-1), to S-trans-geranylated (L-23, 4100 M-1s-1) 2-thioethanesulfonyl fluorides. C10 S-alkyl substitution revealed a kobs/[I] value (1800 M-1s-1) that was 298 times greater than that for PMSF. The compounds induced the degeneration of human neuroblastoma SH-SY5Y cells with EC50 values of 49, 130 and <1000 μM for L-28, L-23 and PMSF, respectively. The increased affinity with the polyisoprenyl derivatization is consistent with the observed substrate specificity and the reported hydrophobic nature of the active site. These results suggest that (1) PMPMEase is a key enzyme for polyisoprenylated protein metabolism, (2) regulation of its activity is essential for maintaining normal cell viability, (3) abnormal activities may be involved in degenerative diseases and cancers and (4) its specific inhibitors may be useful in combating cancers.

We have previously described enhanced human breast cancer cell proliferation and mouse mammary tumor growth induced by α2-adrenergic agonists, associated with α2-adrenoceptor (α2-AR) expression in epithelial cells. The aim of the present work was to assess if stromal fibroblasts can contribute to this effect. α2-AR expression was assessed by immunocytochemistry and immunohistochemistry, cell proliferation by [3H]- Thymidine incorporation and tumor growth by measuring with caliper. All tested mouse and human fibroblasts expressed at least two α2-AR subtypes and α2-adrenergic agonists enhanced fibroblast proliferation. In vivo, the α2-adrenergic agonist clonidine significantly enhanced tumor growth. The α2- adrenergic antagonist rauwolscine reversed this effect, but when administered alone, significantly inhibited tumor growth. Clonidine significantly stimulated cell proliferation in the epithelial-enriched fraction, the cancer associated fibroblastenriched fraction and the co-culture of both fractions in primary cultures from both tumors (IBH-4 and IBH-6). Rauwolscine reversed clonidine stimulation in every fraction. However, when incubated alone, the inhibitory effect was observed in fractions from IBH-4 tumors but not from IBH-6 tumors. These experiments show that fibroblasts from tumor stroma are also influenced by α2-adrenergic compounds through the α2-ARs expressed in these cells. Moreover, the α2-adrenergic antagonist rauwolscine could eventually block in both epithelial and stromal cells, the mitogenic effect of catecholamines released during stress, providing a potential additional treatment for breast cancer patients. Chemists synthesizing adrenergic compounds should consider their action in breast cancer patients.