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Advanced Prostate Cancer

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Prostate Cancer & Hormones - Insulin-like growth factor [IGF] axis.

7 years ago•6 Replies

Apologies for the length of this post. Some bits will be easy - skip the rest.

Much has been written about PCa & insulin-like growth factor [IGF]. Although IGF is associated with PCa risk, studies are not unaminous. For the purpose of this post, I will not dwell on IGF as a causative risk factor, apart from a few key studies. I'm more interested in IGF & progression, & in the IGF receptor as a potential therapeutic target.

However, one must be suspicious of all growth factors. Tall men get more PCa; short men get less. There are growth decision points during childhood. With an uninterrupted supply of good nutrients, the young body will commit to growth. There will be greater exposure to human growth hormone [HGH] & IGF. This seemingly may have an influence on a PCA diagnosis 50+ years down the road.

[1] PCa & Height.

[1a] (2013 - Denmark)

"The association between childhood height and prostate cancer risk was driven by height at age 13 years."

[1b] (2008 - U.K.)

"Height, a marker of childhood environmental exposures, is positively associated with prostate cancer risk, perhaps through the insulin-like growth factor system. "

"Based on the nested case-control, the odds ratio (OR) of prostate-specific antigen-detected prostate cancer per 10 cm increase in height was 1.06 ..."

"There was stronger evidence of an association of height with high-grade prostate cancer (OR: 1.23 ...), mainly due to the leg component, but not with low-grade disease ..."

[1c] (2016 - U.S. - Giovannucci - Health Professionals Follow-up Study)

"In this large prospective cohort study with over 20 years of follow-up, we found taller height to be positively associated with fatal and advanced-stage prostate cancer, in line with prior findings"

"Plausible biological mechanisms for a potential association between body size and prostate cancer involve hormonal and metabolic pathways that interact in a complex manner. These include the insulin/insulin-like growth factor-I (IGF-I) axis, sex hormones, and inflammation-mediated pathways, although the latter remain largely unclear. High levels of IGF-I and insulin have been positively linked to prostate cancer risk and mortality, whereas low testosterone levels have been associated with increased risk of aggressive prostate cancer ..."

[2] IGF & Cell Division.

With growth hormones, there is an increased rate of cell division. Cell division is not without risk. Evolution has given us the Hayflick Limit [2a], which caps the number of times a cell population can divide. The Hayflick phenomenon represents a safety net that seems to recognize that DNA repair mechanisms & cell suicide protocols are insufficient protection against cancer.

[3] IGF Axis.

The components of the IGF axis are:

- IGF-I, IGF-II & insulin itself. The primary interest has been in IGF-I.

- IGF binding proteins [IGFBP], particularly IGFBP-3. Binding proteins reduce levels of free IGF, but they also appear to have independent bioactivity.

- IGF-I Receptor [IGF-IR]. The effects of IGF depend on binding to the receptor. IGF-I has the greatest affinity for IGF-IR binding.

IGF Axis Dysfunction.

Dysfunction can come about from changes in IGF levels, changes in the proportions & levels of the binding proteins, &/or changes in the expression of IGF-IR.

A special note on Insulin.

It is rare to find a pure PCa-Insulin study. The interest lies almost entirely with IGF-I. But it should be noted that long-term diabetics (at least 12 months) have lower PCa rates. This is important for two reasons. First - diabetics get more cancer of every type, except PCa. Second - although pre-diabetics produce high levels of insulin in an attempt to counter insulin resistance, actual diabetics have experienced a burn-out of pancreatic beta cells, & cannot produce normal levels of insulin. Taken together, it certainly looks as though insulin is a PCa risk factor, & uniquely so.

[4] IGF-I in milk.

Milk is the only food that comes with a growth hormone. Perhaps sufficient reason to avoid it as an adult. The IGF-I in cows milk is bioidentical to that of human milk. The milk marketing people put a spin on this by insisting that the IGF-I protein is destroyed in the stomach. This is laughable - why would the hormone be present in milk if it could never get into the blood? What would be the point?

[4a] (2006 - U.K. - Cows' milk & childhood growth.)

"Data on both diet and height were available for 744 children (404 boys) and on diet and IGF for 538 (295 boys). After adjusting for energy, both cows' milk and dairy product intakes were positively associated with IGF-I ... and IGFBP-3 levels ..."

"In boys ... dairy product intake was positively associated with leg length (equivalent to a 0.058 ... standard deviation score increase in leg length per 100 g increase in daily intake)."

IGF-I in cows' milk works. No other protein source is as effective.

[4b] (2009 - U.S.)

"Children in the highest quartile of milk intake (QIV) were taller ..."

"Total protein was not associated with height ..."

"Children who drank milk daily were taller (1.0 cm ...) than those with less frequent intake."

[4c] (2006 - Denmark)

"The strongest evidence that cow's milk stimulates linear growth comes from observational and intervention studies in developing countries that show considerable effects. Additionally, many observational studies from well-nourished populations also show an association between milk intake and growth. These results suggest that milk has a growth-stimulating effect even in situations where the nutrient intake is adequate. This effect is supported by studies that show milk intake stimulates circulating insulin-like growth factor (IGF)-I, which suggests that at least part of the growth-stimulating effects of milk occur through the stimulation of IGFs. Given that the biological purpose of milk is to support the newborn during a period of high growth velocity, such an effect seems plausible."

[4d] (2014 - School of Animal and Comparative Biomedical Sciences University of Arizona) These guys disagree.

"Concerns that IGF-I present in milk could have biological effects on humans have been allayed by studies showing that oral consumption of IGF-I by humans has little or no biological activity. Additionally, concentrations of IGF-I in digestive tract fluids of humans far exceed any IGF-I consumed when drinking milk."

[4e] (2012 - U.K.)

"A cross-sectional analysis of self-reported 12-month dietary intake with serum IGF and IGFBP levels was performed using data from 1,798 subjects screened negative for prostate cancer as part of a UK multicenter trial comparing treatments for this condition."

"For a one standard deviation (SD) increase in dairy product and dairy protein intake, IGF-I increased by 5.28 ng/mL ... and 6.02 ng/mL .., respectively."

"A one SD increase in animal protein was associated with a decrease in IGFBP-2 of 6.20%"

[5] Selective amino acid insufficiency.

The body cannot commit to growth if the building blocks of protein - the essential amino acids - are not present in sufficient quantities.

Protein from meat & fish is "complete" - i.e. it breaks down into all of the necessary amino acids for human protein. Omnivores can severely limit animal protein intake, of course, although I would find that difficuly.

Vegans have more flexibility, since essential amino acids come from different sources. We can synthesize 11 of the 20 basic amino acids, but must get the other 9 from food. Most vegan foods are poor sources of one or more of the 9, but with a variety of foods, a meal can be a rich protein source. On the other hand, one might restrict just one of the 9 & thereby limit protein intake - without necessarily limiting calorie intake. i.e. the diet can be made to be protein-insufficient without further loss of enjoyment. [LOL]

The limiting amino acid in legumes is methionine, & that might be the easiest target.

[5a] (1995 - Belgium - Nutritional regulation of insulin-like growth factor-I.)

"Several lines of evidence indicate that in the human, insulin-like growth factor-I (IGF-I) is nutritionally regulated. Both energy and protein availability are required for maintenance of IGF-I. ... Our findings and those of others in animal models suggest that nutrients influence synthesis and action of IGF-I and its binding proteins (IGFBPs) at multiple levels. In fasting, liver growth hormone (GH) binding is decreased, providing one explanation for decreased IGF-I. In protein restriction, GH receptors are maintained, but there is evidence for a postreceptor defects. The latter results from pretranslational and translational defects. Amino acid availability to the hepatocytes is essential for IGF-I gene expression. Protein malnutrition not only decreases IGF-I production rate, but also enhances its serum clearance and degradation. Finally, there is evidence for selective organ resistance to the growth-promoting effects of IGF-I in protein-restricted rats."

[5b] (2012 - Australia - A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension.)

"Methionine is an essential amino acid with many key roles in mammalian metabolism such as protein synthesis, methylation of DNA and polyamine synthesis. Restriction of methionine may be an important strategy in cancer growth control particularly in cancers that exhibit dependence on methionine for survival and proliferation. ... Several animal studies utilizing a methionine restricted diet have reported inhibition of cancer growth and extension of a healthy life-span. In humans, vegan diets, which can be low in methionine, may prove to be a useful nutritional strategy in cancer growth control. The development of methioninase which depletes circulating levels of methionine may be another useful strategy in limiting cancer growth. The application of nutritional methionine restriction and methioninase in combination with chemotherapeutic regimens is the current focus of clinical studies."

[6] IGF & PCa risk.

[6a] (1999 - U.S. - the Physicians' Health Study)

Edward Giovannucci laid out the epidemiological evidence as it stood in 1999:

"In general, two- to fourfold elevated risks have been observed for prostate cancer in men in the top quartile of IGF-I relative to those in the bottom quartile, and low levels of IGFBP-3 were associated with an approximate doubling of risk."

Followed by Pär Stattin (Sweden) in 2000:

[6b] (2000 - Sweden - Northern Sweden Health and Disease Cohort Study)

"We measured levels of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and insulin in plasma samples from 149 men who had a diagnosis of prostate cancer between 1 month and 10 years after blood collection and among 298 control men."

"Case subjects had statistically significantly higher mean levels of IGF-I than control subjects (229 ng/mL ... versus 214 ng/mL ...)"

"Prostate cancer risk is increased in men with elevated plasma IGF-I. This association was particularly strong in younger men in this study ..."

[6c] (2002 - U.S. - the Physicians' Health Study - Giovannucci)

"Plasma levels of IGF-I and IGFBP-3 were predictors of advanced-stage prostate cancer (RR = 5.1 ... for highest versus lowest quartiles of IGF-I; RR = 0.2 ... for highest versus lowest quartiles of IGFBP-3) but not of early-stage prostate cancer."

"Circulating levels of IGF-I and IGFBP-3 may predict the risk of developing advanced-stage prostate cancer, but their utility for screening patients with incident prostate cancer may be limited."

[7] IGF Binding Proteins.

[7.1] IGFBP-1.

[71a] (2014 - U.S. - Dana-Farber Cancer Institute)

"Elevated IGFBP-1 appears to be associated with shorter time to CRPC and lower overall survival in men with metastatic prostate cancer."

[7.2] IGFBP-2.

[7.2a] (2010 - U.K.)

"We provide evidence that adiposity and change in body shape through the life course are related to the IGF system, with the largest effect of adiposity being to lower IGFBP-2, a possible marker of insulin resistance. The results suggest that circulating IGF-I levels may not be important mediators of the association of adiposity with aggressive prostate cancer, but the role of IGFBP-2 deserves further investigation."

[7.2b] (2011 - U.K.)

"IGFBP-2 promoted cell growth in both cell lines but with PC3 cells this was in an IGF-dependent manner, whereas with DU145 cells the effect was independent of IGF receptor activation."

"IGFBP-2 has a key role in the growth of prostate cancer cells, and silencing IGFBP-2 expression reduced the resistance of these cells to docetaxel. Targeting IGFBP-2 may increase the efficacy of docetaxel."

[7.2c] (2009 - U.S.)

"New evidence indicates that the IGFBPs, irrespective of ligand interactions, correlate with the development and metastatic behavior of several cancers. Increased expression of insulin-like growth factor binding protein 2 (IGFBP-2) is found in advanced cancers of the ovary, breast, stomach, adrenal gland, bladder, CNS, and prostate. Further, IGFBP-2 seemingly has ligand-independent effects that participate in the development and dissemination of advanced cancer cells. As such, IGFBP-2 can assist in the development of the lethal phenotype for some cancers. While several reports have shown an important role for IGFBP-2 in the development of androgen insensitivity and the proliferation of AI PCa cells in vivo, these studies have not tested a role for IGFBP-2 in the metastatic spread of AI PCa cells."

[7.3] IGFBP-3.

[7.3a] (2015 - China)

"IGF-binding protein-3 (IGFBP-3) has been shown to induce apoptosis in an insulin-like growth factor (IGF)‑independent manner in various cell systems, however, the underlying molecular mechanisms remain unknown. In the present study, we showed that IGFBP-3 significantly enhanced interleukin-24 (IL-24)-induced cell death in prostate cancer (PC) cell lines in vitro."

"We propose that the IGFBP-3 and IL-24 non-toxic mTOR inhibitors can be used as an adjuvant in the treatment of PC."

[7.3b] (2014 - China)

"To investigate the effect of inositol hexaphosphate (IP6) on proliferation of human prostate carcinoma LNCaP cells and its relation to insulin-like growth factors binding protein-3 (IGFBP-3) expression."

"Higher expression of IGFBP-3 and lower expression of Bcl-2 in LNCaP cells treated with IP6 were found at both mRNA and protein levels. IP6 treatment enhanced IGFBP-3 mRNA expression by 2.21±0.15 folds."

[7.3c] (2014 - U.S.)

"Insulin-like growth factor binding protein-3 (IGFBP-3), a secretory protein, is the most abundant IGF binding protein present in human serum among all IGF binding proteins. IGFBP-3 shows decreased level of expression in cancerous cells but has been known to be present in significant amounts in normal or non-cancerous cells. IGFBP-3 can induce apoptosis in prostate cancer cells either in an IGF-dependent manner or independently of IGF binding. Although putative cell death specific Insulin-like growth factor binding protein-3 (IGFBP-3R) receptor(s) has recently been identified by which IGFBP-3 may induce its anti-tumor effects, IGFBP-3 has also been known to activate various downstream intracellular signaling molecules via a different mechanistic pathway. Stat-1 has been known to be one of the candidate molecules activated by IGFBP-3. IGFBP-3 can also inhibit Akt/IGF-1 survival pathway in MCF- 7 breast cancer cells which ultimately leads to the induction of apoptosis in these cells. All these studies clearly demonstrate that IGFBP-3 regulates cell proliferation and promotes its pro-apoptotic effects in cancer cells in two different pathways,1) sequester IGF-I to bind to IGF-I receptor to inhibit cell proliferation and induce apoptosis, 2) independent of IGF-I pathway, IGFBP-3 binds to some putative receptor and activate various downstream pro-apoptotic molecules involved in cell death."

[7.3d] (2011 - U.S.)

"Nuclear factor-kappaB (NF-κB) is constitutively activated in a variety of human cancers including prostate cancer and involved in tumorigenesis, tumor progression and chemo-resistance. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a potent tumor suppressor and is significantly suppressed in a variety of cancers. Diverse biological effects of IGFBP-3 have been reported to be both dependent and independent of the IGF/IGF-I receptor (IGF-IR) axis. The precise underlying mechanisms of IGF/IGF-IR-independent, antiproliferative actions of IGFBP-3 are yet to be elucidated. We found an inverse correlation between NF-κB activity and IGFBP-3 expression during prostate cancer progression using an in vitro prostate cancer progression model. Restoration of IGFBP-3 resulted in significant inhibition of constitutively elevated NF-κB activity in prostate cancer cells."

[8] IGF & Mortality.

[8a] (2012 - U.K.)

"Many studies have reported associations of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with prostate cancer development, but none have investigated their association with fatal progression of prostate cancer."

I certainly find that odd.

"In men with advanced cancer, there was some evidence that IGF-I was positively associated (HR 1.20 ...) and IGFBP-3 was inversely associated (HR 0.84 ...) with all-cause mortality after controlling for age, treatment status, smoking, prostate-specific antigen and Gleason grade at diagnosis."

"There was some evidence that IGF-I was positively associated with prostate cancer mortality in advanced cases (HR 1.23 ...)"

"Measures of IGF-I and IGFBP-3 may have potential as prognostic markers in predicting risk of death in men with advanced prostate cancer."

[9] IGF-IR Antibodies.

[9a] (2015 - U.S.)

"We present a patient who participated in a Phase II study of an antagonist antibody to insulin-like growth factor 1 receptor (IGF-1R) in men with mCRPC and experienced over five years of stable disease. His disease was rapidly progressing before exposure to the antibody and resumed its aggressive behavior following discontinuation of therapy, strongly supporting the attribution of his stable disease to IGF-1R inhibition. His pre-treatment biopsy exhibited increased protein expression of IGF-1R ... Consequently, agents that target IGF-1R may provide profound and durable responses in a subset of patients"

{"Thirty years ago, at the age of 47 years, our patient was diagnosed with metastatic prostate cancer to the bone when he presented with acute back pain. Remarkably, 3 mg per day of diethylstilbestrol (DES) taken orally maintained disease stability for 24 years, at which time his PSA began to rise despite a castrate level of testosterone (28 ng/dl). His bone scan showed metastatic disease to the thoracic spine, sternum, and multiple ribs. His prostate gland was biopsied for the first time after the development of mCRPC and revealed the features consistent with high-grade prostate adenocarcinoma, Gleason’s Grade 4 + 4 = 8."}

"Phase II studies of IGF-1R in prostate cancer have shown some promise, but there are currently no Phase III studies of IGF-1R inhibitors ... Our patient’s study enrolled 31 patients and revealed disease control lasting more than six months in nine (29%) in the every-two-week dosing and three (30%) in the every-three-week dosing. The longest disease control, other than our patient, was four years, so there was a subset of patients who clearly benefited."

[9b] Preclinical Targeting IGF-IR signaling in Prostate Cancer [Table 1]

GF-IR signaling in Prostate Cancer

(i) IMC-A12 (Cixutumumab)

Full human mAb induce IGF-IR internalization

Inhibits AD and AI tumor growth by inducing cell cycle arrest

Enhance castration effect on AD tumor growth

Combined therapy with Docetaxel enhanced treatment effect on AI LuCaP35V and LuCaP 23.1 in comparison to monotherapy

"Cixutumumab (formerly IMC-A12), a fully human IgG1 monoclonal antibody, was shown to induce internalization of IGF-IR. Cixutumumab was tested extensively for prostate cancer therapy with preclinical androgen-dependent (AD), androgen-independent (AI), and osseous human prostate cancer models. Alone, cixutumumab can induce cell cycle arrest of both AD and AI tumor cells and the effect of castration can be enhanced by delay of progression to AI tumors. Cixutumumab can also enhance the effect of docetaxel as combined therapy through enhanced negative regulation of genes associated with cell cycle progression, survival and therapeutic resistance. Goel et al recently showed that the VEGF/VEGF receptor neuropilin-2 (NRP2) signaling can repress the expression of IGF-IR at transcriptional level and thus IGF-IR signaling in prostate cancer cells. Combined therapy of co-targeting NRP2 with shRNA and IGF-IR with cixutumumab resulted in synergistic effect and complete inhibition of PC-3 tumor growth in vivo, whereas mono-therapy only showed minimal or moderate effect. Because of the compensatory relation between NRP2 and IGF-IR expression, NRP2 is proposed to be a robust biomarker for predicting responses to IGF-IR therapy."

(ii) AMG479 (Genitumab)Full human mAb, Inhibits IGF binds to IGF-IR

Treatment alone retard VCaP growth with enhanced therapeutic effect when combined with castration. No effect on AI CWR- 22RV1

"Ganitumab (formerly AMG 479), a fully human antibody that inhibits binding of IGF-I and IGF-II to IGF-IR, is a newly developed IGF-IR blockade that has been tested for prostate cancer therapy in preclinical models. Ganitumab was shown to inhibit ligand-induced phosphorylation of IGF-IR and the downstream effector AKT resulting in reduced proliferation of multiple androgen-dependent and castration-resistant human prostate cancer cell lines in vitro. It was shown that ganitumab treatment alone retarded androgen-dependent VCaP prostate tumor growth and blocked the growth of castration-resistant VCaP xenografts for over 11.5 weeks of treatment. When combined with castration, ganitumab showed a potent therapeutic effect and achieved a long period suppression of VCaP xenograft growth. Ganitumab alone did not have appreciable therapeutic effect in established castration-resistant CWR-22Rv1 xenograft tumor. However, very recent study by Galet et al showed that when combined with calorie restricted diet, Ganitumab showed significant inhibition of tumor growth of CWR-22Rv1 xenografts ..."

(iii) ATL 1101Antisense oligonucleotide, suppress IGF-IR expression

Monotherapy suppress PC-3 tumor growth and delays LNCaP progression to CRPC

"To date the only small molecule targeting human IGF-IR for prostate cancer therapy was ATL1101, a 2′-MOE-modified antisense oligonucleotide. In vitro study showed that ATL1101 suppressed proliferation and increased apoptosis in PC-3 and LNCaP cells in androgen-deprived conditions. ATL1101 also showed in vivo suppression of PC-3 tumor growth and delaying castration-resistant progression of LNCaP xenografts ..."

...

"Our assessment ... is that the approach to IGF-IR inhibition is probably best achieved in combination, either early with the initiation of ADT or perhaps with more extensive study with cytotoxic chemotherapy. "

[10] Zinc & the IGF System.

[10a] (2009 - India)

"Zinc significantly reduces the cell viability of PC-3 cells. It decreases the protein levels of IGF-IR ... and increases the level of IGFBP-3."

"This study suggests that zinc decreases the survival of androgen-independent prostate cancer cells by modulating the expression of IGF system components and its signaling molecules. Thus, zinc may be qualified as a potential agent for the treatment of prostate cancer."

[10b] ( 2011 - Poland)

"A significantly lowered Zn/PSA ratio appears to be a sensitive marker of neoplastic lesions, PCa and PIN, regardless of age. In men under 65 years, the Zn/IGF-1 ratio was reduced, depending on the stage of neoplastic lesions (PIN>PCa)."

[11] Lycopene & IGF.

[11a] ( 2007 - India)

"PC-3 cells treated with lycopene showed a significant decrease in cell proliferation. Lycopene, at a dose of 40 microM, significantly increased the level of IGFBP-3."

"There was a significant decrease in the IGF-IR expression after the cells were treated with lycopene and IGF-I."

[12] Apigenin & IGF.

[12a] (2011 - U.S.)

"... administration of apigenin resulted in substantial reduction in the levels of IGF-I and increase in the levels of IGFBP-3 in the serum and the dorso-lateral prostate. This modulation of IGF/IGFBP-3 was associated with an inhibition of p-Akt and p-ERK1/2."

-Patrick

[1a] ncbi.nlm.nih.gov/pubmed/240...

[1b] ncbi.nlm.nih.gov/pubmed/187...

[1c] ncbi.nlm.nih.gov/pmc/articl...

[2a] en.wikipedia.org/wiki/Hayfl...

[4a] ncbi.nlm.nih.gov/pubmed/166...

[4b] ncbi.nlm.nih.gov/pubmed/192...

[4c] ncbi.nlm.nih.gov/pubmed/168...

[4d] ncbi.nlm.nih.gov/pubmed/246...

[4e] ncbi.nlm.nih.gov/pubmed/225...

[5a] ncbi.nlm.nih.gov/pubmed/747...

[5b] ncbi.nlm.nih.gov/pubmed/223...