Prostate
From the outset, prostate cancer has been a highly promising target for phenoxodiol (PXD), based on a range of mechanisms of action that have particular application in this form of cancer.
The following is divided into four parts. The first part is a background look at prostate cancer, in particular those aspects of the disease that are relevant to PXD and how it works. The second part looks at those mechanisms of action and why they make PXD such a promising drug candidate for this disease. The third part reviews previous and current clinical experience with PXD in prostate cancer. Finally, the fourth part is a personal musing on the best way to use PXD in prostate cancer.
BACKGROUND
This is not meant to be a complete guide to prostate cancer, just a review of certain key aspects of the disease that help us understand why PXD might be a successful drug in this disease, and future directions for determining how best to use the drug.
1. Structure of the prostate.
The prostate is composed of two main types of cells – epithelial glandular cells and stromal cells. The epithelial cells (stained purple in the diagram below) are organised into ducts (or tunnels) and their role is to produce the prostatic secretions that will eventually be mixed with the sperm at the time of ejaculation to provide nourishment to the sperm. The stromal cells (stained red) are mainly smooth muscle cells and their role is to provide a supporting scaffold for the glandular ducts and to contract to expel the glandular secretion during ejaculation.
2. Prostate disease.
The two most common disorders of the prostate are prostate cancer (or carcinoma), arising from the glandular cells, and benign prostatic hypertrophy (or BPH) due to excessive build-up of both the glandular and the stromal smooth muscle cells. The link, if any, between these two conditions that accompany ageing in men is uncertain, although they do share one aspect in common, and that is that there is a ‘switching-off’ of cell death processes.
Prostate cancer is thought to be a disease process spanning many years, representing an accumulative effect of separate insults commencing from the time a man reaches adulthood. The first signs of the disease are evident at a relatively young age with pockets of premalignant cells displaying slight physical and behavioural changes (known as dysplasia). Dysplasia is not of itself a concern, and for the majority of men it never developed further than this. However, for about 1 in 6 men in developed countries, those premalignant cells undergo the final steps that convert them into fully-fledged cancer cells. The risk factors that tip premalignant prostate cells over the edge are not well defined, although genetic predisposition, exposure to environmental carcinogens, hormonal factors, and lifestyle factors such as diet and stress are all implicated.
Once cancerous, prostate cancer cells in common with most other forms of cancer have three main characteristics:
- they ignore key incoming regulatory messages from the body, particularly those messages that keep them well-behaved;
- they have a propensity to migrate from their original position; and
- they override their internal self-destruct mechanism (known as apoptosis) that normally would be triggered if the cell became irreversibly damaged or in response to the body’s normal regulatory controls.
BPH is characterised by accumulation of glandular epithelial cells and stromal smooth muscle cells. This is a benign condition that affects a high proportion of men in later life, typically leading to obstruction to urine flow. Originally thought to be the result of a proliferation of prostate cells, the condition now appears to be due to an inability of cells to die. That is, new cells are being created at a normal rate, but the older cells are remaining and accumulating rather than dying off at their allocated use-by date, something that BPH has in common with prostate cancer. The cause of BPH also is not well understood, although a changing ratio of male:female sex hormones in the ageing male body is believed to be the main underlying cause
3. Association between glandular and stromal cells.
The two main types of cells in the prostate, despite having completely separate functions, are highly inter-dependent. Both cell types are in close communication with each other, exchanging chemical signals to the extent that the growth and function of each tissue is dependent on the other.
To that extent, the initiation and the growth of prostate cancer cannot be considered in isolation as a purely glandular epithelium event. Research suggests a role for the stroma at certain key points in the carcinogenesis process. Whether prostate cancer is associated with a failure of the stroma to stop injury to the glandular cells, or whether it is the stroma itself that is inducing injury, is not known.
4. Role of testosterone.
Testosterone, the main male sex hormone, is a key player in the promotion of prostate cancer.
In the normal prostate gland, testosterone is primarily responsible for driving the function and growth of both the glandular and stromal cells. Coming mainly from the testes, testosterone is converted within prostate cells by the enzyme, 5-a-reductase, into the more powerful, dihydrotestosterone, that interacts with hormone receptors on the nuclear membrane to induce prostate cells to divide.
Once prostate cancer develops, testosterone remains an important driver of growth for the great majority of cancer cells. Cancers at this time are referred to as being androgen-dependent. With time, that responsiveness to testosterone diminishes at which time the cancer is to referred to as being androgen-independent, where growth will occur regardless of the presence or absence of testosterone.
Androgen-deprivation therapy is an important treatment tool in the early stages of prostate cancer. That is accomplished either by lowering testosterone levels in the blood (either surgical castration or blocking the testes from producing testosterone) or blocking the binding of testosterone to their receptors.
5. Treatment of prostate cancer.
Surgical removal of the prostate gland (prostatectomy) remains the most likely cure of this disease, providing that the disease is contained to the gland. Spread (metastasis) from the gland usually occurs either through direct migration out through the gland capsule to surrounding pelvic tissues, or by passage along the prostate nerves to the spine.
Where metastasis has occurred, there are three main treatment options, typically used sequentially.
The first of these is radiation. Prostate cancer cells in most patients are highly sensitive to radiation damage. Radiotherapy usually is delivered by external beam therapy with or without localised radiotherapy (known as brachytherapy).
The second option where radiotherapy fails is androgen-deprivation therapy, slowing tumour growth or even shrinking tumours. This effect typically lasts 1-2 years.
The third option is chemotherapy. Prostate cancer cells typically are poorly sensitive to chemotoxic drugs. The two drugs most commonly used in cases of advanced prostate cancer are docetaxel and cisplatin, either alone or in combination. Response rates to chemotherapy vary, but typically any benefit is of relatively short duration.
BIOLOGICAL EFFECTS OF PHENOXODIOL
1. PXD kills prostate cancer cells.
PXD is highly cytotoxic to human prostate cancer cells. The initial effect of PXD is to block prostate cancer cells from dividing, which it does by increasing the activity of genes that block cell division (cyclin D1 and p21waf/CIP1) and decreasing the activity of genes that promote cell division (CDK2). This is followed within 24-48 hr by cell death through both death processes of necrosis and apoptosis.
PXD has no known adverse effects on normal prostate cells.
2. PXD blocks the stimulatory effect of testosterone.
Experiments were conducted to look at the biological effects of PXD on both glandular and stromal elements within the prostate. This was done with whole rat prostate glands in organ culture.
Testosterone alone caused a significant increase in the numbers of both glandular and stromal cells. PXD antagonised this effect, significantly blocking the development of the entire glandular structure of ducts, and causing almost complete ablation of stromal smooth muscle cells.
The fact that the inhibitory effect of PXD reduced cell numbers substantially lower than that of the control gland, indicated that this effect was more than that of a simple anti-androgenic effect. In the stroma, PXD caused almost complete ablation of smooth muscle cells and a significant increase in the rate of apoptosis of these cells, whether testosterone was present or not.
This points to an ability of PXD to interfere in the reciprocal communication between the galndular cells and the stromal cells, a normal biological process that is up-regulated by testosterone, and thought to be fundamental to the development of dysplasia as a pre-carcinogenic event.
3. PXD is an anti-androgen.
PXD is a moderately potent inhibitor of two enzymes that are instrumental in the function of testosterone. 17-b-hydroxysteroid dehydrogenase is a crucial enzyme involved in the production of testosterone in the testes, and 5-a-reductase (as we noted earlier) is important for converting testosterone within the prostate to the more active dihydrotestosterone. In both cases PXD is inhibiting enzyme activity at levels that are present in the blood of patients receiving PXD therapy.
4. PXD enhances sensitivity to chemotherapies.
PXD enhances the sensitivity and reverses multi-drug resistance of a wide range of cancer cell types, including prostate cancer cells, to standard chemotoxic drugs such as cisplatin and docetaxel. [This aspect of PXD biology is discussed separately on this website.]
A particularly pertinent recently reported study (British Journal of Cancer, 100, 649-655, 2009) found that a combination of PXD and cisplatin was significantly synergistic in athymic mice bearing human prostate cancer cells as a result of PXD causing a 35% increase in the uptake of cisplatin by the cancer cells and a corresponding 300% increase in the number of DNA adducts in those cancer cells.
CLINICAL RESULTS
A key step in taking PXD into the clinic for use in patients with prostate cancer was to show that the strong anti-cancer effect of PXD seen in the test-tube held true in the whole animal, and more particularly whether PXD could deliver a strong anti-cancer effect when delivered orally. This was confirmed when athymic mice bearing either androgen-dependent or androgen-independent human prostate cancer cell lines were treated with PXD, resulting in significant slowing of tumour growth.
On the back of this promising pre-clinical data, a small sighting Phase 2a study was conducted in Australia in 2002 to see whether the anti-cancer effect in mice would translate into an effect in humans. That study looked at the effect of PXD as a monotherapy in 26 patients with late-stage, androgen-independent prostate cancer.
Despite the limited number of patients, an anti-cancer effect was reported. The study showed that PXD delivered a dose-response effect on the progression of the disease, with the 2 higher dosages (200 and 400 mg) giving statistically significant (p<0.05) better outcomes than the 2 lower (20 and 80 mg) dosages. The results of that trial were reported in 2004 as per the following table.
| Phenoxodiol | n | PSA doubling time | Time to disease progression |
| (mg per dose) | (weeks) | (weeks) | |
| 20 | 6 | 14 | 13 |
| 80 | 6 | 22 | 17 |
| 200 | 5 | 66+ | 66+ |
| 400 | 9 | 39++ | 42++ |
+ One patient remained on phenoxodiol therapy with stable PSA levels at week 88
++ Three patients remained on phenoxodiol therapy with stable PSA levels at 40, 72 and 80 weeks.
A reasonable question stemming from the Australian study was, if PXD is capable of inhibiting the progression of advanced prostate cancer, then shouldn’t it be even more effective against early-stage disease? And answering this question of when PXD would deliver maximum benefit seems to be a prime objective of the current Yale-Harvard Phase 2 study, the early results of which were announced in February 2009.
Two distinct groups of patients are being tested in the current study, representing two separate progressive points in the cancer process. The target population is patients with an aggressive form of prostate cancer, where localized therapy (radiotherapy or prostatectomy) has failed as evidenced by a subsequent rise in PSA levels. One group of patients in the Yale-Harvard study is at an early stage following failure of localized treatment (Group B), while the second group (Group A), similar to those patients used in the Australian study, is patients whose cancers have progressed to the point of being androgen-independent. The median PSA levels for the two groups in the patients enrolled to date are 7.6 and 38.5 ng/mL respectively, indicating the difference in disease progression between the two groups.
With just 25 patients reported on (16 in Group A, 9 in Group B), the data is preliminary. Nevertheless, this early data suggests that the confidence of the Company in PXD as a treatment for prostate cancer is not misplaced.
Taking the Group A (later-stage) patients first. The conference abstract combined with the Company’s announcement speaks of definitive results for only 6 of the 16 enrolled patients; 4 showed disease progression and 2 showed a response (1 patient showing a >50% decline in PSA levels and the other showing no disease progression for > 6 months). Presumably the remaining 10 patients in this group were still receiving therapy at the time of the conference. About the best that you could say about such small numbers is it is encouraging that any patients with such advanced disease would show any response to PXD monotherapy, confirming what was seen in the earlier Australian study. Whether this trend continues with greater patient numbers remains to be seen.
The numbers look somewhat better in Group B, with 5 of the 9 patients reportedly having stabilized disease (i.e. no PSA rise) for a median of 3 months. What is not clear from the conference abstract is whether that figure of 3 months represents the median time before all patients went on to have PSA rises, or whether that represents the median time up until the time of the conference that patients had stabilized disease. Regardless, it suggests a clinical response from a chemotherapy at a point in the disease process where the use of standard chemotherapies would never be considered because of their toxic side-effects.
MUSINGS
As we have noted elsewhere, the way that you select to use a drug for the purpose of bringing it to market may not necessarily be the best way to use that drug or the way that it ultimately comes to be used in common practice. It all boils down to expediency in terms of gaining regulatory approval, as well as the sort of knowledge about the drug that only comes with extensive on-market use.
The current Yale-Harvard clinical trial should provide critical direction in this regard when the trial is completed in the next12 months, but in the meantime, these are some thoughts on the subject.
(a) Late-stage, metastatic, androgen-independent prostate cancer.
These patients are Group A in the current Yale-Harvard study. The current approved treatment for these patients is a combination of docetaxel (Taxotere) + prednisone, approved by the FDA in May 2004. That approval was based on the outcome of a large clinical study comparing docetaxel + prednisone to mitoxantrone + prednisone (the approved treatment at that time) where a small survival advantage was demonstrated. The median survival times of the two treatment arms were 18.9 versus 16.4 months respectively.
The problem that I see in pursuing this indication is in the unknowns still to be answered and the long time (and cost) that it would take to address them. The main unknown is whether to continue to use PXD as a monotherapy (as the current Yale-Harvard study is doing) or to use it in combination with docetaxel or cisplatin (as pre-clinical studies suggest that it should). Answering this first question could be done on the basis of PSA levels and/or the occurrence of new metastases, but it would nevertheless still require a fairly lengthy Phase 2b study. Having answered that question, answering the next question of whether it would provide increased survival over docetaxel + prednisone would require a large pivotal study running over a number of years to cater for a minimum mean survival time of about 18 months.
(b) Recurrence following localised treatment.
This is the second group of patients in the Yale-Harvard study, with all available evidence pointing to it being the most likely indication to pursue in terms of a registration trial:
- first, because the current data from the Yale-Harvard study indicates that PXD is delivering meaningful clinical benefit for these patients;
- second, because there currently is no approved therapeutic options for patients at this stage of the disease;
- third, because the safety of PXD means that a chemotoxic drug can be used without concern in patients with early-stage disease;
- fourth, the likely end-point in any such study would have to do with rising PSA levels over a relatively short period of time.
(c) Adjunctive localised treatment.
This is not in any way a realistic option for registration purposes, but it is how I would want to be using the drug if I was in the position of being diagnosed with inoperable prostate cancer.
Novogen patent applications indicate that PXD is a potential radio-sensitising agent. That is, it has the capacity to enhance the damaging effect of radiation on cancer cells. Commencing PXD therapy in conjunction with radiotherapy would offer the dual advantages of enhancing the cytotoxic effect of the radiotherapy, while at the same time providing an independent cytotoxic effect on a developing cancer as opposed to a later, established cancer.
I don’t for any minute think that anyone is going to go down this path of testing in the foreseeable future, but I have little doubt that it is where PXD will ultimately find its preferred application.
OTHER RESEARCH
Finally, out of interest, a couple of recent publications that draw attention to the natural role of isoflavones in the biology of the prostate. I always hesitate to mention these sorts of dietary studies because from experience I know that some people immediately draw the inference that PXD, or any of the Company’s drugs for that matter, fall into some sort of herbal category because the principle of isoflavonoid drug development derives from a natural phenomenon.
But to do so would be to say equally that docetaxel, one of the most common anti-cancer drugs in use today, and the standard therapy for patients with late-stage prostate cancer, is herbal because it is a semi-synthetic derivative of Taxol, a naturally-occurring chemical compound originally extracted from the bark of the Pacific yew tree. Or that most of the current antibiotics and antifungal agents are herbal because they are based on naturally-occurring compounds such as penicillin.
The following two publications do nothing more than serve to emphasise the fact that the utility of isoflavonoid drugs such as PXD in the treatment of prostate cancer has its basis in rational biological phenomena.
The first of these publications finds that the prostate gland actively concentrates dietary isoflavones to levels 6-times that of blood. This concurs with Novogen findings that PXD is concentrated in prostate cancer tissue, suggesting an active pumping mechanism that simply underscores the likely role of isoflavones in the maintenance of prostate health.
THE PROSTATE Vol. 69, 2009
Prostatic soy isoflavone concentrations exceed serum levels after dietary supplementation.
Gardner CD et al.
Department of Medicine, Stanford Prevention Research Center, Stanford University Medical School, Stanford, California 94305, USA
Abstract: BACKGROUND: The effects of soy isoflavones on prostate cancer may be concentration-dependent. The impact of soy supplementation on isoflavone concentrations in prostate tissues and serum remain unclear. OBJECTIVE: To assess and compare concentrations of soy isoflavones in prostate tissue and serum among 19 men with prostate cancer who had elected to undergo radical prostatectomy. METHODS: Participants were randomized to receive either daily soy supplements (82 mg/day aglycone equivalents) or placebos for 2 weeks (14 days) prior to surgery. Serum samples were obtained at the time of the surgery. Isoflavone concentrations were measured by HPLC/ESI-MS-MS. RESULTS: The median (25th, 75th percentile) total isoflavone concentration in the isoflavone-supplemented group was 2.3 micromol/L (1.2, 6.9) in the prostate tissue and 0.7 micromol/L (0.2, 1.2) in the serum. Total isoflavone concentrations in this group were an average of approximately 6-fold higher in prostate tissue compared to serum; the tissue versus serum ratio was significantly lower for genistein than daidzein, 4-fold versus 10-fold, P = 0.003. Tissue and serum levels of isoflavones among the placebo group were negligible with a few exceptions. CONCLUSIONS: The findings from the present study suggest that prostate tissue may have the ability to concentrate dietary soy isoflavones to potentially anti-carcinogenic levels.
The second publication draws a link between relatively high levels of isoflavone metabolites in blood and a lower risk of developing prostate cancer.
Inoue, S. Sasazuki and S.Tsugane.
Plasma Isoflavones and Subsequent Risk of Prostate Cancer in a Nested Case-Control Study: The Japan Public Health Center.
Journal of Clinical Oncology. 2008 20 Dec; 2636: 5923-5929.
Purpose: The incidence of prostate cancer is much lower in Japanese than Western populations. Given the preventive effects of isoflavones on carcinogenesis in the prostate in many non-human studies and the high consumption of isoflavones in Japanese, this low incidence may be partly due to the effects of soy.
Patients and Methods: We conducted a nested case control study within the Japan Public Health Center-based
Prospective Study: A total of 14,203 men aged 40 to 69 years who had returned the baseline questionnaire and provided blood samples were observed from 1990 to 2005. During a mean of 12.8 years of follow-up, 201 newly diagnosed prostate cancers were identified. Two matched controls for each case were selected from the cohort. Conditional logistic regression model was used to estimate the odds ratios (ORs) and 95% CIs for prostate cancer in relation to plasma levels of isoflavone.
Results: Plasma genistein level tended to be inversely associated with the risk of total prostate cancer. Although plasma daidzein showed no association, the highest tertile for plasma equol, a metabolite of daidzein, was significantlyassociated with a decreased risk of total prostate cancer (OR = 0.60; 95% CI, 0.36 to 0.99; Ptrend = .04). These inverse associations were strengthened after analysis was confined to localized cases, with ORs in the highest group of plasma genistein and equol compared with the lowest of 0.54 (95% CI, 0.29 to 1.01; Ptrend = .03) and 0.43 (95% CI, 0.22 to 0.82; Ptrend = .02), respectively. Plasma isoflavone levels were not statistically significantly associated with the risk of advanced prostate cancer.
Conclusion: Isoflavones may prevent the development of prostate cancer.
Copyright 2008 by American Society of Clinical Oncology.