Antiproliferative Effect of SST Analogs on Gep Net

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Evidence for antiproliferative properties of somatostatin and its analogs derives from in vitro and in vivo studies. Somatostatin can exert both cytotoxic and cytostatic actions. It has been demonstrated that it mediated arrest at the Glphase of the cell cycle and that this effect is mediated through activation of sstr-2 and sstr-5.3, 3,24

The antiproliferative effects of SST analogs on GEP NET may be the result of direct and indirect actions (Fig. l).33

Somatostatin Analogues

Faiss et al15 showed that ultra-high-dose lanreotide treatment in patients with metastatic GEP NET, progressive under previous therapies (e.g., low-dose somatostatin analogs and/or interferon-a), can generate an additional antiproliferative effect especially in patients with midgut tumor disease. Thus, dose escalation of somatostatin analogs up to ultra-high doses as used in the study represents a useful therapeutic adjuvant in metastatic neuroendocrine tumor disease following conventional therapy.

In contrast to foregut and midgut tumors, they15 did not observe an antiproliferative effect in hindgut tumors. This confirms the long-stadning hypothesis that metastatic hindgut tumors are refractory to all forms of medical therapies including somatostatin analogs despite the expression of somatostatin receptors in vivo. This again raises the issue that, in addition to the expression of somatostatin receptors in neuroendocrine tumor cells, other humoral and/or cellular components must be involved.15

Further studies are needed to assess the exact role of SST analogs in induction of apoptosis and control of growth in GEP NETs. Currently, no convincing evidence exists to support the use of SST analogs at high doses.

Direct Effects of SST on Cell Growth

Somatostatin and its analogs may directly inhibit tumor cell growth by interacting with specific somatostatin receptors located on tumor cells.

Analyses of sstr mRNAs demonstrate that various human tumors from neuroendocrine and gastroenteropancreatic origin express various sstr mRNA, each tumor expressing more than one subtype, sstr-2 being the most frequently expressed.9,25

The presence of somatostatin receptors in tumors argues in favor of a direct role for somatostatin in the regulation of tumor growth. A direct inhibitory effect of somatostatin or analogs on cell growth has been demonstrated on various cancer cell lines which express endogenous somatostatin receptors (cells of mammary, pancreatic, gastric, lung, colorectal or thyroid origin). However, the mechanisms ofcell growth arrest induced by SST are still poorly understood.9,26 The direct inhibitory action of SST on cell growth may result from the blockade of mitoge-nic growth factor signal. The antiproliferative effect of somatostatin can also result from apoptosis. Apoptosis has been reported to be induced by the sstr-3 subtype via a G protein-dependent signaling and to be associated with an intracellular acidification and activation of endonuclease and induction of p53 and Bax.9,27,28

Imam et al29 evaluated apoptotic effects of octreotide on neuroendocrine tumors using BON-1, a human serotonin-secreting pancreatic endocrine tumor cell line xenografted into nude mice. They showed on increase in apoptotic cells in mice receiving treatment with high dose octreotide compared with a placebo group. In parallel to their preclinical study, Imam et al29 also studied apoptosis of tissue samples in patients with neuroendocrine tumors treated with high doses of lanreotide. After 6 and 12 months of treatment, patients receiving high-dose SST analog showed a biochemical response (decrease in different neuroendocrine tumor markers) and an increase in apoptotic index (AI). Therefore the treatment with high-dose SST analogs may induce apoptosis in NET, while this was not found during treatment with low-dose SST analogs.29

Besides the antiproliferative effect of somatostatin due to cell growth arrest and apoptosis, SST may directly control cell growth by inhibiting the synthesis and the secretion of autocrine growth factors, cytokines and hormones involved in the proliferation of tumor cells. It is well known that the aberrant expression of growth factors, cytokines or hormones and their receptors represent fundamental circuits that may induce uncontrolled growth and metastatic behavior of cancer cells.9

Indirect Effects of SST on Cell Growth

The indirect antineoplastic effects of somatostatin and its analogs are independent of the presence of SST receptors on the tumor cells. Therefore, a possible beneficial effect of somatostatin analog therapy is not restricted to tumors expressing SST receptors.2

Indirect effects of somatostatin on tumor cell growth may be the result of inhibition of secrection of growth-promoting hormones and growth factors which stimulate the growth of various types of cancer. It is known that tumors depend on specific growth factors for their growth.9 Insulin-like growth factor-1 (IGF-1) is an important modulator of many neoplasms that express IGF-1 receptors. Octreotide has been demonstrated to negatively control IGF-1 level. In addition, a direct effect on IGF gene expression has also been reported.9'30

Somatostatin and its analogs can also indirectly control tumor development and metastasis by inhibition of angiogenesis. They inhibit angiogenesis in vitro and in vivo.9'31 Somatostatin and its receptors may play a regulatory role in hemodynamic tumor-host interactions and vascular drainage.9

Evidence suggests that SST may influence the immune system. Somatostatin and receptors are expressed in human lymphoid organs and can regulate various immune functions including lymphocyte proliferation' immunoglobulin synthesis' and cytokine production. It has been well demonstrated that SS and its analogs inhibit the proliferation of human and rat lymphocytes in vitro. However, there is no information available on the effect of somatostatin in vivo on the immune system.9'32

Control of Tumor Growth in GEP NET

SST analogs show antitumor activity in a variety of experimental models both in vivo and in vitro.33'34 However, tumor shrinkage in GEP NET has rarely been observed, but SST analogs have been reported to induce tumor volume stabilisation in 25-75% of patients with neuroendocrine tumors.15,35-42 Faiss et al15 studied a group of 30 patients with metastatic GEP NET who underwent ultra-high-dose (15 mg/d) lanreotide therapy and evaluated tumor growth every 3 months. After a 1-year treatment period one complete and one partial remission were observed in patients with functional midgut NET. Eleven patients had stable disease and 11 patients showed continuing tumor growth.15 Shojamanesh et al35 showed that SS analogs have antitumor growth effects in patients with malignant pancreatic NET. Fifteen patients with malignant gastrinoma were treated initially with octreotide, 200 |g every 12 hours, and at last follow-up were being maintained on long-acting octreotide, 20-30 mg every month. 47% of studied patients demonstrated tumor stabilization and 6% a decrease in tumor size. The growth response was long-lasting, the mean duration of response was 25.0+/-6.1 months.35

Control of tumor growth occurs in approximately 50% of VIPoma patients treated with octreotide. However, the reduction in the size of liver metastases secondary to VIPomas is temporary and transient and control of tumor growth in response to octreotide therapy is lost after 8-16 months of treatment.2

Aparicio et al43 confirmed an antitumor activity of SS analog treatment resulted in 57% of cases of tumor stabilisation in 35 patients with progressive NET. They (ref. 43) stated that somatostatin analogs produce an inhibitory effect that leads to tumor stabilisation in most patients with "slowly progressing" NET. The authors (ref. 43) suggested determining the pre-treatment slope of the tumor growth rate (STGR) as a useful yardstick for selecting patients likely to benefit from SST analog therapy. NET differentiation, the primary tumor site, the carcinoid syndrome and the intensity of octreoscan uptake are also potential predictive factors for response to somatostatin analog therapy.43

Eriksson et al37 reported one major response and disease stabilisation in 70% of 19 cases of GEP NETs over a median duration of 12 months. Nine of the patients in this study had previously been treated with standard doses of octreotide suggesting a possible benefit of dose escalation. Moreover, no enhanced antitumor effect was gained by administering higher doses of SST analogs. The dose-response effect is still poorly understood. The authors37 stated that no conclusion can be drawn given the small number of patients. Variations in tumor stabilization rates between studies could be explained by the great heterogeneity of NET patients (Table 1).

Table 1. Antitumor activity of somatostatin analogs activity of somatostatin analogs in patients with NETs

Median

Duration

No of

Tumors

Tumors

of Response

Patients

Drug

Regression

Stabilisation

[Months]

Salz et al36

34

250 ^g octreotide

0%

50%

5

1993

3x daily

Arnold38

52

200 ^g octreotide

0%

37%

18

1996

3x daily

Eriksson37

19

750 - 12000 ^g/day

5%

70%

12

1997

lancreotide

Faiss15

30

5 mg lancreotide

3 %

37 %

1999

3x daily

Ducreux40

39

30 mg/every 14 days

5%

49%

9,5

2000

Aparicio43

35

100 ^g octreotide

3 %

57%

11

2001

3x daily 30 mg lancreotide every 14 days or both

(76%-slowly 33%-rapidly progressing NET)

Faiss39

SS analogs

25

1 mg lancreotide

4%

25%

12

2003

3x daily;

1 mg lancreotide

7.1%

28%

12

3x daily+interferon-a

5 x 106 IU 3 times

a week

Welin44

12

Octreotide pamoate

75%

12

2004

160 mg every 2 weeks

Recently, Faiss et al39 showed in the prospective, randomized, multicenter study for the first time that somatostatin analogs, interferon alpha, or the combination of the two had comparable antiproliferative effects in the treatment of metastatic neuroendocrine gastroenteropancreatic tumors. Response rates were lower compared with those published in previous, nonrandomized studies. The antiproliferative effect of the tested substances was similar for functional and nonfunctional neuroendocrine tumors.

Most of the studies are comparable in the sense that patients with progressive disease were included. Partial tumor regression was a rare event and stabilization of tumor growth the most favourable result occurring in patients with GEP NET. However, even stable disease is relatively short-lasting since growth inhibition was reported to last for 2-60 months.3

Influence of SST Analogs on Survival of Patients with GEP NET

There is, as yet, no published study that shows that therapy with somatostatin analogs, as the only treatment, improves survival.18 The overall five year survival for pancreatic NETs is 50-80%, with insulinoma and gastrinoma having up to 94% five-year survival, although clearly there is large variation depending on the stage at presentation and whether curative surgery is possible.8 The 5-year survival rates of patients with neuroendocrine tumors is less than 20% when liver metastases are present. Furthermore, the median survival for patients with malignant carcinoid tumors with the carcinoid syndrome is less than 2 years from the time of diagnosis.18

The long-term treatment of patients with carcinoid syndrome with octreotide has resulted in an increase of median progression-free survival from 3.5 to 15 months. The duration of the remission can be short (median 8-12 months), and the early development of tachyphylaxis is not uncommon.45

The majority of centers working with patients with neuroendocrine tumors use a multimodal therapeutic approach. Thus, it is very unlikely that a patient with a neuroendocrine tumor will receive a somatostatin analog as the only treatment during the clinical course of the disease.18 To date, no prospective randomized trial has been performed in patients with GEP NETs treated with SST analogs compared with observation. Additional studies are necessary to determine any convincing effect of SST analogs on survival.1

Adverse Reactions to SST Analog Therapy

The most common side-effects of somatostatin analog are generally mild and include nausea, transient abdominal cramps, flatulence, diarrhea and local reaction at the injection site. Most of these minor side-effects resolve with time. In 2-50% of patients gall stones are formed de novo, but these remain virtually always asymptomatic. Rare, more severe adverse events of octreotide therapy include hypocalcemia, bradycardia, acute pancreatitis, hepatitis, jaundice, transitory ischemic attacks, and a negative inotropic effect of the analogs.18,4

Tachyphylaxis and Resistance to SST Analogs

Desensitization to the effect of SST analogs within weeks or months has been observed in the majority of GEP NET-bearing patients, on important difference existing between patients with respect to the induction of the tumor type-dependent tachyphylaxis phenomenon.33,47

Potential mechanisms of tachyphylaxis and resistance to somatostatin analog therapy in patients with sst receptor-positive tumors are: receptor down-regulation, desensitization (a decrease in responsiveness due to receptor uncoupling from second messenger activation), nonhomogeneous expression of sstr in tumors, outgrowth of sstr-negative cell clones, resistance due to tachyphylaxis of the inhibitory effect of SST analogs on indirect tumor growth-promoting mechanisms and mutations in sstr genes leading to the absence of functional receptor proteins.46,47

Tumor-Targeted Radioactive SST Analog Treatment

The high expression of sstr in endocrine tumors has provided the molecular basis for the successful use of radiolabelled octreotide or lanreotide analogs as tumor tracers in nuclear medicine for diagnosis and radiotherapy (see also Chapter 7). This is a useful palliative option for symptomatic patients with inoperable or metastatic tumor. The principle of treatment is only to give radionuclide therapy when there is abnormally increased uptake of the corresponding imaging agent. No randomised controlled trials have yet been performed.8,33

Peptide receptors scintigraphy with a radioactive somatostatin analog (111In-DTPA-octreotide) is a sensitive and specific technique to identify in vivo the presence and abundance of somatostatin receptors in various tumors. The method has now been accepted as an important tool for the staging and localization of neuroendocrine tumors. However, the technique is currently being evaluated as a possible means of targeting neuroendocrine tumors with "tumor-targeted" radiotherapy using a repeated administration of high doses of 111In-DTPA-octreotide.18 Therapy with 1 1In-pentetreotide in the progressive metastatic NET (performed in three centres, n = 81 patients) resulted in stable disease in 57% of patients.49 The ability of sstr receptors to internalize initiated the development of sst receptor-targeted radiotherapy with radiolabelled somatostatin analogs using the p-emitter yttrium- 90 [90Y-DOTA0,Tyr3]octreotide] (OctreoTher), [90Y-DOTA]-lanreotide and lutenium177 [177Lu-DOTA0,Tyr3]octreotate.33

Therapy with somatostatin analogs coupled to p-emitting radionuclides, such as 90Y and 177Lu, is potentially more effective, as higher tumor radiation doses can be achieved and the longer range of the p-particles (1-10 mm) may also lead to radiation of neighbouring receptor-negative tumor cells.49

Although there is a need for more accurate prediction of the absorbed doses, treatment with all mIn-, 90Y- or Lu-labelled SS analogs has been associated with considerable symptomatic improvement with limited side effects that are mainly related to kidney function.50 (See also Chapter 7).

New SST Analogs and Future Developments

SOM230 is a new somatostatin analog with high binding affinity to human somatostatin 1,2,3 and sstr-5 receptors. Based on the multiligand binding properties of SOM230, on its prolonged inhibition of hormone secretion in animal models and on the expression of multiple SST receptors in GEP tumors, more patients with GEP NET could be treated successfully with SOM230 without experiencing tachyphylaxis during chronic therapy.7,51 SOM230 had no agonist activity at the sstr-4, in line with lack of affinity for this subtype. This SST analog was particularly potent at sstr-5 compared with octreotide.7 As SOM230 strongly inhibits cAMP production by stimulating sstr-1 and sstr-5 and multiple SST receptors are expressed in GEP NET, SOM230 could have a greater inhibitory effect than octreotide on hormones secreted by carcinoid tumors. Moreover, SOM230 may be the only pharmacological treatment for GEP tumor patients who are not responsive to currently available therapy, either because they do not express sstr-2 or because targeting these receptors does not translate into clinical efficacy.7,52,53

SST analogs have also been used as carriers to deliver cytotoxic agents to cancer cells. Therapy studies with radiolabelled somatostatin analogs linked with cytotoxic compounds have so far been carried out in experimental tumor models only but they are very promising.33,49 Schally et al54 synthesised new targeted cytotoxic somatostatin octapeptide conjugates such as RC-121 and RC-160 coupled to doxorubicin or its superactive derivative 2-pyrrolino-DOX (AN-201). AN-238, which contains AN-201 linked to the carrier RC-121, has been demonstrated to be very effective on a variety of human experimental cancer models.

Recently, a new approach with a genetic radioisotope targeting strategy has been proposed, based on the induction of sst2 receptor expression and the selective tumor uptake of radiolabeled peptides.55 Of particular importance in the future is the need to exploit the major advances in gene therapy to optimize the full potential of somatostatin analogs in the management of neoplasia.2

The combination of somatostatin analogs with interferons and cytotoxic agents in randomized clinical trials is also worthy of investigation.18 Combination therapy of somatostatin analogs with cytotoxics or other hormonal treatments targeted somatostatin analog chemotherapy or radiotherapy in both advanced malignancy and in the adjuvant setting may prove to be very much more effective than somatostatin analog monotherapy. Carefully controlled clinical studies with objective outcome measures are required to evaluate combination therapies.2

Recently intensive research is also focused on the development of new peptidic and non-peptidic somatostatin analogs, selective agonists for each receptor subtype and pansomatostatin analogs with a binding profile similar to that of the natural peptide.

These compounds might help in the characterisation of unsuspected biological activities and new indications for somatostatin. In the future, they will probably improve the diagnosis and treatment of neuroendocrine tumors.33,56

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