Prostatepedia Weekly 9.28.18
Prostatepedia Weekly 9.21.18
Prostatepedia Weekly 9.14.18
Low Testosterone and Prostate Cancer: Is the Protection Real? - European Urology
Prostate Cancer Screening: No Effect on Overall Mortality:
Screening for prostate cancer may result in a small absolute benefit in
disease-specific mortality over 10 years but does not improve overall
mortality.
Gallium-68 PET/CT scans prior to first-line treatment of some men with prostate cancer | THE "NEW" PROSTATE CANCER INFOLINK:
A newly-reported set of data from an Australian clinical research team
has now shown that 68Ga PSMA PET/CT scans changed the staging and the
management of men after initial diagnosis and prior to f…
ASCO endorses AUA/ASTRO/SUO guidelines on treatment of localized prostate cancer | THE "NEW" PROSTATE CANCER INFOLINK:
We are delighted to note that the American Society of Clinical Oncology
(ASCO) has now endorsed 66 of the 68 guidelines issued in April 2017 on
the treatment of localized prostate cancer by a joint…
Gallium-68 PET/CT scans prior to first-line treatment of some men with prostate cancer | THE "NEW" PROSTATE CANCER INFOLINK:
A newly-reported set of data from an Australian clinical research team
has now shown that 68Ga PSMA PET/CT scans changed the staging and the
management of men after initial diagnosis and prior to f…
Computer-aided
classification of prostate cancer grade groups from MRI images using
texture features and stacked sparse autoencoder - ScienceDirect: A
novel method to determine the Grade Group (GG) in prostate cancer (PCa)
using multi-parametric magnetic resonance imaging (mpMRI) biomarkers is
inv
Study: Hormone Therapy Can Make Prostate Cancer Worse in Some Patients | Cooking with Kathy Man:
Scientists at Cedars-Sinai have discovered how prostate cancer can
sometimes withstand and outwit a standard hormone therapy, causing the
cancer to spread. Their findings also point to a simple blo…
What prostate cancer awareness means to Dr. Alicia Morgans | THE "NEW" PROSTATE CANCER INFOLINK:
Alicia Morgans, MD, MPH, is a medical oncologist who specializes in
prostate cancer management at Northwestern University Feinberg School of
Medicine in Chicago, Illinois, where she is an associate
Imaging of distant metastases of prostate cancer | SpringerLink:
The detection of distant metastases at the initial diagnosis of
prostate cancer (PCa) establishes the treatment approach and has a
prognostic value, nevertheless it is not well established. Since...
Addressing Challenges to Adopting MRI for Prostate Cancer Screening | Newsroom | Weill Cornell Medicine:
Magnetic resonance imaging (MRI) may not be the best diagnostic choice
universally for all men suspected of having prostate cancer, according
to researchers at Weill Cornell Medicine and NewYork-Presbyterian.
Hypothetical cost savings associated with “observation” for low-risk prostate cancer | THE "NEW" PROSTATE CANCER INFOLINK:
A newly published article in JAMA Oncology has reported hypothetical
costs savings to Medicare of $320 million over a 3-year time frame if
men of > 70 years with low-risk prostate cancer are sim…
Direct mechanical characterization of prostate tissue—a systematic review - Kelly - - The Prostate - Wiley Online Library
But annual, mass, population-based PSA screening really works (or does it?) | THE "NEW" PROSTATE CANCER INFOLINK:
A new and potentially controversial article in Urology (the “Gold
Journal”) has just suggested that regular, mass, population-based
screening of men for risk of prostate cancer every 12…
Complications of Androgen Deprivation Therapy in Men With Prostate Cancer: Page 2 of 2 | Cancer Network:
This article summarizes the key side effects associated with ADT for
the treatment of prostate cancer and discusses strategies to optimize
management.
New trial (S1802) for treatment of men with newly diagnosed, metastatic prostate cancer | THE "NEW" PROSTATE CANCER INFOLINK:
Earlier this month we had mentioned hearing about a new trial to
explore whether local ablation of the primary tumor could improve the
outcomes of men initially diagnosed with metastatic prostate c…
68Ga-PSMA-11 PET: Better at Detecting Prostate Cancer than Multiparametric MRI? | Radiology
Dismissing Reduced Abiraterone Dose Is 'Absolutely Wrong':
By taking a prostate cancer drug with food, patients can use a quarter
of the dose. But an editorial dismissed the idea, which angered a
prominent expert.
Androgen Receptor-Targeted Treatments for Prostate Cancer: 35 Years' Progress with Antiandrogens - E. David Crawford: Androgen Receptor-Targeted Treatments for Prostate Cancer: 35 Years' Progress with Antiandrogens
Active surveillance for localized prostate cancer. Nationwide, observational study - The Journal of Urology: The objective of this study was to investigate nationwide survival outcomes in men
with localized prostate cancer managed on active surveillance.
What to Expect When Active Surveillance Leads to Prostatectomy | Medpage Today: High-risk features in 39% of prostate specimens at surgery
Defining Intermediate-Risk Prostate Cancer Suitable for Active Surveillance - The Journal of Urology: Active surveillance (AS) for intermediate-risk prostate cancer (PCa) is controversial.
Many AS programs are limited to grade group (GG) 1 (Gleason 6) and PSA<10 ng/ml. However,
recent guidelines state that AS can be considered for limited GG2 (Gleason 3+4), despite
limited data on outcomes. Our objective was to compare prostatectomy outcomes between
subgroups of intermediate-risk versus low-risk PCa.
Worth
a local treatment? – Analysis of modern radiotherapy concepts for
oligometastatic prostate cancer | Radiation Oncology | Full Text:
Prostate cancer (PCA) is the most-prevalent non-skin cancer in men
worldwide. Nevertheless, the treatment of oligometastatic, especially
lymph-node (ln) recurrent, PCA remains elusive. The aim of our study was
to provide insights in radiotherapy (RT)-treatment of recurrent PCA
exhibiting ln- or osseous (oss)-oligometastases. Between April 2012 and
April 2017, 27 oligometastatic PCA patients (19 ln and 8 single oss)
were treated with RT at our institution. The metastasis-free survival
(MFS) was 24.8 m (22.0–36.0 m) and 25.4 m (23.9–28.1 m) for the ln- and
oss-subgroup resulting in 1-year MFS of 75.4 and 100% and 2-year MFS of
58.7 and 83.3% for ln- and oss-metastatic patients, respectively. Of
notice, none of the recurrences for ln-patients was in the RT-field,
constituting a local control of 100%. Within the ln-group, pre-RT
median-PSA was 2.6 ng/ml, median post-RT PSA was 0.3 ng/ml, which was
significant (p = 0.003). Median biochemical-free survival (bfS) was
12.2 m. PCA that was initially confined to the prostate had a better bfS
(p < 0.001) and MFS (p = 0.013). The oss-group had a median PSA
of 4.9 ng/ml pre-treatment which dropped to a median value of 0.14 ng/ml
(p = 0.004). To
ANO7 Gene Linked to Aggressive Prostate Cancer | Cancer Network:
By elevating the expression of ANO7, a potential prostate cancer
susceptibility gene, it may be possible to predict disease severity and
outcome.
Total
Medicare Costs Associated With Diagnosis and Treatment of Prostate
Cancer in Elderly Men | Oncology | JAMA Oncology | JAMA Network:
This large cohort study uses the SEER-Medicare database to evaluate the
Medicare costs associated with diagnosis and treatment of nonmetastatic
prostate cancer in men 70 years or older.
High Anxiety with Active Surveillance in Prostate Cancer? Not Really | Medpage Today: In my case, the first week after diagnosis was bad, but that was it
External Validation of Prostate MRI QCAD/Lyon - Full Text View - ClinicalTrials.gov: External Validation of Prostate MRI QCAD/Lyon - Full Text View.
Open- Label
Trial of Sipuleucel-T Administered to Active Surveillance Patients for
Newly Diagnosed Prostate Cancer - Full Text View - ClinicalTrials.gov:
Open- Label Trial of Sipuleucel-T Administered to Active Surveillance
Patients for Newly Diagnosed Prostate Cancer - Full Text View.
More Doctors Say Men Should Think Twice about Prostate Cancer Screening | Cooking with Kathy Man:
Lisa Rapaport wrote . . . . . . . . . Most men shouldn’t get routine
prostate cancer screening because the potential benefits are small and
there are clear harms, an international panel of experts …
An Integrative Approach to Prostate Cancer | The Journal of Alternative and Complementary Medicine
Complications of Androgen Deprivation Therapy in Men With Prostate Cancer | Cancer Network:
This article summarizes the key side effects associated with ADT for
the treatment of prostate cancer and discusses strategies to optimize
management.
Ac-225-PSMA-617: another update | THE "NEW" PROSTATE CANCER INFOLINK:
One of the more exciting new developments in radiopharmaceuticals for
metastatic prostate cancer has been the development of alpha-particle
emitters attached to PSMA ligands. We previously reported…
Optimal Control to Develop Therapeutic Strategies for Metastatic Castrate Resistant Prostate Cancer - ScienceDirect:
In metastatic castrate resistant prostate cancer (mCRPC), abiraterone
is conventionally administered continuously at maximal tolerated dose
until trea…
Ac-225-PSMA-617: another update | THE "NEW" PROSTATE CANCER INFOLINK:
One of the more exciting new developments in radiopharmaceuticals for
metastatic prostate cancer has been the development of alpha-particle
emitters attached to PSMA ligands. We previously reported…
Three-dimensional localization and targeting of prostate can... : Current Opinion in Urology:
d follow-up. However, the accuracy of MRI to detect clinically
significant disease is variable between different institutions. The role
of quality control initiatives to increase the concordance between
clinical-imaging–histopathological data and to improve accurate
targeting of the suspicious lesions cannot be overemphasized. This
article describes the approaches to correlate mpMRI findings with
histopathology and the role of multidisciplinary teams for quality
improvement and feedback interventions.
Recent findings
Validating
the mpMRI and image-targeted fusion biopsy findings with prostatectomy
specimen histopathology as the gold standard is essential for assessment
of the concordance between clinical-imaging–histopathological data.
Utilization of a MRI-derived patient-specific prostate mold enables a
direct comparison between histopathological versus imaging
characteristics of cancer foci in the same sectional plane of the
specimen versus MRI. Furthermore, ‘reverse fusion’ technology provides
the ability to audit the quality of targeting following fusion biopsy.
Summary
The development of a multidisciplinary team approach with group discussions, workflows to integrate and cor
MRI to guide biopsies or avoid biopsies? : Current Opinion in Urology:
of care for men with increased suspicion for prostate cancer, MRI with
or without targeted biopsy has been shown to reliably improve the
detection of clinically significant disease following a prior negative
biopsy. At the same time, there is a growing body of evidence to support
the use of MRI for diagnostic purposes in biopsy-naive patients, as
well for enrolling and monitoring men on active surveillance programs.
Summary
mpMRI
is an evolving technology with great promise for altering our approach
to prostate cancer diagnosis and surveillance. In conjunction with
targeted biopsies, MRI offers greater specificity for the detection of
clinically significant cancer and therefore may help to reduce
overdetection of indolent disease while minimizing the risks and
limitations of systematic biopsies.
Saturday, September 29, 2018
Sunday, September 9, 2018
Some New Prostate Cancer News Stories of Interest
Contents
The Next IPCSG Meeting
Saturday September 15, 2018 10:00 AM
Dr. Carl Rossi Update
on Proton Therapy
Dr. Rossi has personally treated more than 9,000
prostate cancer patients with proton radiation over the last 26 years—more than
any other physician in the world.
Internationally recognized for his achievements in
cancer treatment, Dr. Rossi is a radiation oncologist with a research focus on
the quality of life and cure rate in prostate cancer and lymphoma. Specializing
in proton beam therapy, he has been treating prostate cancer patients with
proton therapy since 1991. Prior to serving as the Medical Director of
California Protons, he was the Medical Director of the Scripps Proton Therapy
Center and was an Associate Professor in the Department of Radiation Medicine
at the Loma Linda University Medical Center.
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Participation in a patient support group increases prostate cancer patient knowledge
Posted on August 15, 2018 by Sitemaster
A newly published study from a group of German
researchers examined the degree to which participation in patient support group
activities increased prostate cancer patients’ health literacy and,
specifically, their prostate cancer‐specific and non‐cancer‐specific knowledge
about health care.
Unlike a lot of studies in this area, which often
enroll only small numbers of patients, this study [https://onlinelibrary.wiley.com/doi/abs/10.1002/pon.4854]
by Haack et al., at Hannover and Hamburg in Germany, enrolled nearly 600
participants in total, so the results should be pretty reliable.
Here are the basic data from the study:
·
There were 576 participants in total
·
441 were prostate cancer support group members
(Group A)
·
135 were prostate cancer patients who had not
participated in a support group (Group B)
·
Compared to the patients in Group B, the
patients in Group A had:
·
Greater knowledge about prostate cancer in
general (odds ratio [ OR] = 2.2)
·
Heard about specific guidelines related to
prostate cancer (OR = 3.7)
·
Actually read one or more guidelines (OR = 5.1)
·
Greater competence regarding navigation of heath
services (OR = 1.8)
·
Patients in Group A and Group B had similar
levels of knowledge about non-cancer-related health care knowledge.
We should emphasize, of course, that one can become
very knowledgeable about prostate cancer and how health care systems work
without every actually participating in a patient support group of any type
(prostate cancer-specific or otherwise). However, on the other hand, the
authors conclude that participation in a prostate cancer-specific support group
seems to provide an important platform for information exchange in the field of
[prostate cancer]. The potentially conflicting results on PC knowledge and the
application‐skills may arise from the different forms of measurement —
knowledge was tested, skills were self‐assessed.
What this study did not test, however, is whether the
benefits of participation in “live” prostate cancer support groups that meet on
a regular basis was any more beneficial than participation in the various (and
evolving) forms of on-line and phone-based support groups, and the degree to
which participation in support groups increased the probability that patients
would choose forms of management (over time) most suited to their individual
needs.
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ww.medscape.com
MRI-Based PIRADS Score Aids in Diagnosis of Prostate Cancer
By Reuters Staff
August 16, 2018
NEW YORK (Reuters Health) - Higher PIRADS scores are
associated with a higher likelihood of diagnosis of prostate cancer, according
to a retrospective study.
The Prostate Imaging Reporting and Data System
(PIRADS) score classifies MRI lesions on a scale from 1 to 5, which reflects
their level of suspicion from least to most. PIRADS 3 lesions are considered
equivocal.
Dr. Niranjan J. Sathianathen and colleagues from the
University of Minnesota, in Minneapolis, investigated the correlation between
PIRADS 3-5 scores and the diagnosis of clinically significant and all prostate
cancer for three common biopsy indications: biopsy-naive patients, patients with
previous negative transrectal ultrasound (TRUS) biopsy, and active-surveillance
patients.
Prostate cancer of any grade was found in 51.9%, 26.5%
and 43.8% of patients, respectively.
Overall cancer-detection rates were 7.7% for PIRADS
scores 1-2, 29.7% for PIRADS 3, 42.3% for PIRADS 4 and 82.4% for PIRADS 5, the
team reports in Prostate Cancer and Prostatic Diseases, online July 23.
The detection rate for clinically significant cancers
was 30.1% among biopsy-naive men, 15.7% among those with a previous negative
biopsy and 19.5% among those on active surveillance.
Clinically significant cancers were found in 0% of men
with PIRADS scores between 1 and 2, in 8.9% of those with a PIRADS score of 3,
in 21.4% of those with a PIRADS score of 4 and in 62.7% of men with a PIRADS
score of 5.
The accuracy of PIRADS scores (as measured by area
under the receiver operator curves) was 0.69 for the diagnosis of any cancer
and 0.74 for the diagnosis of clinically significant cancer.
Men who had a previous negative biopsy had lower
detection rates for any prostate cancer for PIRADS 3 and 4 lesions compared
with men who were biopsy naive or on active surveillance.
"Overall and clinically significant cancer
detection rates are correlated with PIRADS score on multiparametric MRI,"
the researchers conclude. "Biopsy yield is also dependent on the clinical
setting and this should be considered in the decision-making process when
determining the need for biopsy."
"Moreover, it is important for institutions to
audit their own cancer detection rates due to the multiple confounders which
impact cancer detection rates," they add. "Avoiding biopsy of PIRADS
3 lesions appears to be safest in men with prior negative biopsy as it risks
missing diagnosis of the fewest significant cancers."
Dr. Sathianathen did not respond to a request for
comments.
SOURCE: https://bit.ly/2MGe6nk
Prostate Cancer Prostatic Dis 2018.
Reuters Health Information © 2018
Cite this article: MRI-Based PIRADS Score Aids in
Diagnosis of Prostate Cancer - Medscape - Aug 14, 2018.
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What are the natural ways to prevent prostate cancer?
Last
reviewed Thu 16 August 2018
By
Scott Harris
Reviewed
by Daniel Murrell, MD
Can you prevent prostate cancer? Natural
ways to lower risk What to avoid Risk factors Get regular testing Takeaway
There
is no single best way to prevent prostate cancer, but several natural methods
can help. These include maintaining a healthful weight, exercising, and eating
plenty of fruits and vegetables.
After
skin cancer, prostate cancer is the type most common among American men,
according to the Centers for Disease Control and Prevention (CDC). For the
majority, prostate cancer is not fatal.
The
American Cancer Society estimate that males with prostate cancer have a 5-year
survival rate of 99 percent.
Prostate
cancer can still carry serious consequences for quality of life and may be
life-threatening.
In
this article, we describe several natural steps a person can take to reduce
their risk of developing prostate cancer.
Can
you prevent prostate cancer?
Adding
soy products to the diet may reduce the risk of developing prostate cancer.
It
is not possible to prevent prostate cancer, but it is possible to reduce a
person's risk.
Most
natural methods of reducing this risk are safe if a person follows a doctor's
instructions and has no allergic response.
Incorporate
these methods into a broader care plan, and speak with a doctor beforehand.
The
best ways to reduce the risk of developing prostate cancer are to make positive
changes involving diet and exercise, according to the American Cancer Society.
If
a person tries to reduce their risk in other ways, these are less likely to be
effective without a healthful diet and exercise program.
Natural
ways to lower risk
Researchers
continue to investigate the potential for medications and natural remedies to
reduce the risk of prostate cancer.
The
following drugs may be effective:
·
finasteride
(Proscar)
·
dutasteride
(Avodart)
·
aspirin
However,
no study to date definitively demonstrates that any drugs can eliminate the
risk.
In
recent years, rigorous biomedical research has tested the effectiveness of
natural remedies. For example, results of laboratory studies have suggested
that saw palmetto has beneficial properties. However, it is not an effective
treatment for prostate cancer.
Below
are some natural remedies that are commonly used to lower the risk of prostate
cancer.
Soy
products
Isoflavones
are a chemical compound with anti-inflammatory properties. The foods with the
highest concentrations of isoflavones are soybean products, including:
·
tofu
·
soy
milk
·
miso
Other
foods that contain isoflavones include:
·
chickpeas
·
beans
·
alfalfa
A
2016 study concluded that isoflavones could benefit health in several ways,
including helping to protect against prostate cancer.
The
medical community currently holds that, while isoflavones cannot treat or
prevent the disease, they can play a protective role.
Omega-3
fatty acids
Omega-3
fatty acids are present in fish and other types of seafood. Additional sources
include:
·
walnuts
·
flax
seeds
·
soybeans
There
is some evidence that omega-3s fatty acids may reduce prostate cancer risk.
However,
many experts no longer believe that the acids have significant cancer-fighting
properties.
Tomatoes
variety
of tomatoes on a board
Studies
suggest that tomato consumption may lead to a reduced risk of prostate cancer.
Processed
tomatoes, including all cooked and canned varieties, contain a compound called
lycopene.
Some
studies suggest that this compound may reduce the risk of cancers, especially
those of the prostate, lung, and stomach.
A
review from 2016 found that increased tomato consumption resulted in a reduced risk
of prostate cancer, though the authors note that more research is needed.
Grapefruit,
watermelon, and apricots also contain lycopene.
Coffee
In
2016, researchers published a review of 105 studies that considered the effects
of coffee on cancer risk.
They
concluded that coffee and its antioxidant capabilities may reduce the risk of
developing prostate cancer and some other types of the disease.
What foods are
good for an enlarged prostate?
A
person can reduce inflammation by making changes to the diet. This can support
the functioning of the prostate, and it may prevent cancer. If a person has an
enlarged prostate, certain foods may help. Learn about these foods here.
What
to avoid
Some
compounds in foods may increase a person's risk of developing prostate cancer.
Consider
avoiding the following:
Selenium and
vitamin E
The
medical community once considered selenium and vitamin E to be opponents of
cancer.
However,
more recent research suggests that these compounds, when taken together or in
isolation, can increase the risk of prostate cancer in some people.
Anyone
concerned about prostate cancer should avoid supplements containing vitamin E
or selenium.
Vegetable oils
A
diet excessively high in fat can increase the risk of many types of cancer, and
the omega-6 fatty acids in vegetable oils may promote the growth of prostate
cancer cells.
Oils
derived from corn, sunflowers, safflowers, cottonseed, and soybeans, for
example, can contain substantial amounts of omega-6 fatty acids.
Grilled or fried
meats
The
National Cancer Institute in the United States advises against eating meats
cooked at high temperatures, typically by grilling or frying.
When
a person cooks muscle meat, including beef, pork, and poultry, at high
temperatures, the meat may form chemicals that cause changes in DNA, resulting
in an increased risk of cancer.
Sugar and
carbohydrates
The
glycemic load and glycemic index measurements show how quickly carbohydrates
and sugars affect a person's blood sugar and insulin.
Some
studies have suggested that a diet with a high glycemic load may increase the
risk of developing prostate cancer.
The
Dana-Farber Cancer Institute report that, while the relationship between sugar
and cancer remains complex, sugar may have the highest impact on the risk of
prostate, colorectal and pancreatic cancers.
Risk factors
People
aged 65 years of age or older account for many cases of prostate cancer.
Risk
factors for prostate cancer include:
·
Age.
Approximately 60 percent of all prostate cancer diagnoses occur in males aged 65
or older.
·
Genetics.
The highest rates of prostate cancer in the U.S. occur in African-American men,
followed by men who are Caucasian, Hispanic, American Indian/Alaska Native, and
Asian/Pacific Islander, respectively.
·
Diet.
A diet rich in fat and low in fruits and vegetables increases the risk of
prostate cancer.
·
Environment.
Exposure to some industrial chemicals also increases this risk.
·
Family
history. If a father or brother has had prostate cancer, a person has more than
twice the risk of developing it.
Get
regular testing
A
lifestyle that includes exercise and a healthful diet can help to reduce the
risk of prostate cancer.
However,
attending regular checkups and screenings is still the best way to handle this
risk.
Speak
with a doctor before trying natural or alternative ways to prevent cancer.
Takeaway
While
it is not possible to prevent prostate cancer, some lifestyle changes and
natural compounds may reduce a person's risk.
Anyone
concerned about their prostate cancer risk should attend regular checkups and
screenings.
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New genetic marker could help diagnose aggressive prostate cancer
Date: August 30, 2018
Source: University of Turku
Summary: A new link has been found between certain genetic
mutations, the aggressiveness of prostate cancer, risk of developing the
disease and poorer survival rates of patients.
Scientists
have discovered a link between certain genetic mutations, the aggressiveness of
prostate cancer, risk of developing the disease and poorer survival rates of
patients. The gene, called ANO7, could play a vital role in improving diagnosis
of prostate cancer patients.
There
is currently no clear way to diagnose aggressive prostate cancer at an
early-stage. Genetic mutations, such as those revealed in this study, could
lead to the development of accurate diagnostic tests that will ultimately mean
patients receive the best possible treatment, sooner.
The
researchers studied the DNA from over 1,700 prostate cancer patients and a
comparable number of healthy men to look for genetic mutations that were
associated with the disease. They were particularly interested in studying
mutations to the ANO7 gene because their previous research suggested this could
be a gene of interest for prostate cancer.
"We
found that small genetic changes to the ANO7 gene increase a patient's risk of
aggressive prostate cancer. One of the current biggest unmet needs in prostate
cancer care is being able to diagnose aggressive cancers at an early stage.
Genetic testing for ANO7 could help identify these patients sooner and may
bring new opportunities for precision oncology in prostate cancer," says
the leading author of the study, Professor Johanna Schleutker from the
Institute of Biomedicine of the University of Turku, Finland.
The
researchers found one particular genetic mutation that correlated with an
increased risk of developing prostate cancer as well as the severity of the
disease. They also found a separate mutation that correlated with shorter
survival.
Analysis
of tissue samples from prostate tumours revealed that mutations to ANO7 were
associated with the gene being more active, suggesting that the biological
function of ANO7 may play an important role in why these cancers are more
aggressive. The function of ANO7 is not fully understood, but further research
could lead to new ways to treat the disease.
Although
the study involved a large population, it is limited by the fact that it is
primarily a Caucasian population from Northern Europe. Further research
involving other demographics is needed to validate the findings. The research
was published in the International Journal of Cancer. The study was funded by
the Worldwide Cancer Research in Britain, the Cancer Foundation, Academy of
Finland, Sigrid Jusélius Foundation, and Government research funding granted by
Turku University Hospital.
Story
Source:
Materials
provided by University of Turku. Note: Content may be edited for style and
length.
Journal
Reference:
·
Elina
Kaikkonen, Tommi Rantapero, Qin Zhang, Pekka Taimen, Virpi Laitinen, Markku
Kallajoki, Dhanaprakash Jambulingam, Otto Ettala, Juha Knaapila, Peter J.
Boström, Gudrun Wahlström, Csilla Sipeky, Juha-Pekka Pursiheimo, Teuvo Tammela,
Pirkko-Liisa Kellokumpu-Lehtinen, Vidal Fey, Lovise Maehle, Fredrik Wiklund,
Gong-Hong Wei, Johanna Schleutker. ANO7 is associated with aggressive prostate
cancer. International Journal of Cancer, 2018; DOI: 10.1002/ijc.31746
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The androgen-sensitive to androgen-resistant transition: an hypothesis
Posted
on September 5, 2018
A
media release issued on Tuesday this week by a usually highly respected medical
center in the Los Angeles area is misleadingly entitled, “Hormone therapy can
make prostate cancer worse, study finds”.
The
fact that men treated with androgen deprivation therapy (ADT) can and do
progress, quickly or much less quickly, by becoming androgen resistant, and
that, in some of those cases, this occurs because of the development of
neuroendocrine forms of prostate cancer, is not news, by any manner of means,
and the implied suggestion that researchers at Cedars-Sinai Medical Center have
just made this discovery is unfortunate at best. (See here for the actual media
release.)
What
the research team at Cedars-Sinai actually have done is propose a possible
mechanism explaining why and how ADT can induce the transformation of
androgen-sensitive prostate adenocarcinoma cells into androgen-resistant
neuroendocrine cancer cells. And the title of the paper by Mishra et al. (just
published in the Journal of Clinical Investigation) that reports their findings
and their hypothesis is [Stromal epigenetic alterations
drive metabolic and neuroendocrine prostate cancer reprogramming].
The paper itself is very clear that transition from androgen-sensitive to
androgen-resistant forms of prostate cancer is a common and well-known effect
of ADT.
MIshra
et al. report detailed findings — based on studies in laboratory mice — about
how certain epigenetic effects on prostatic cancer-associated fibroblasts
(PCAFs, a specific type of cell found in men with prostate cancer) can lead to
secretion of abnormal levels of glutamine, and that there is a clearly higher
level of serum glutamine in mice that are resistant to ADT than in those which
are responsive to ADT (with an odds ratio [OR] = 7.45). They further postulate
that epigenetic regulation of Ras activity in PCAFs is associated with a gene
identified as RASAL3, and that expression of this gene and the consequent rise
in serum glutamine levels is or at least may be a biomarker for metabolic and
neuroendocrine reprogramming in some prostate cancer patients who become
resistant to standard forms of ADT. This hypothesis is still to be validated in
actual prostate cancer patients (as far as we can tell).
We
wish to be very clear that the work reported by Mishra et al. is of
considerable interest since it may help us to develop new and better forms of
test for the onset of neuroendocrine prostate cancer and for treatment for at
least a subset of men who start to become castration-resistant after either
orchiectomy or other standard forms of medical castration. However, we also
wish to point out that the media release issued by Cedars-Sinai spends four
paragraphs implying that no one knew about the transition from
androgen-sensitive adenocarcinona to androgen-resistant neuroendocrine
carcinoma, which has been well understood for years based on research at
centers like the University of California, San Francisco (UCSF), the Johns
Hopkins Medical Center in Baltimore, and others.
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Why does hormone therapy worsen some prostate cancers?
Published 9/6/18
By Catharine
Paddock PhD
Fact checked by
Jasmin Collier
Hormone
therapy for prostate cancer does not always work; the tumor can become
resistant and continue to spread. Now, new research reveals how the therapy
alters the environment of tumor cells to make this happen.
Hormone therapy
can actually make some prostate cancers worse, but how?
Scientists
at the Cedars-Sinai Medical Center in Los Angeles, CA, suggest that their study
could lead to a "simple blood test" to identify prostate cancer cases
that are likely to become resistant and aggressive if they are treated with
hormone therapy.
They
report their findings in a study paper that now features in the Journal of
Clinical Investigation.
Prostate
cancer starts in the prostate, which is a gland that lies between a man's
bladder and his penis, next to the rectum. The gland surrounds the urethra,
which is the tube that carries urine from the bladder to the penis. It makes
and adds fluid to semen as it passes through this tube.
The
cancer begins when cells in the prostate grow out of control and form a tumor.
It arises mostly in men aged 65 and older and rarely before the age of 40.
In
the United States, prostate cancer is the most common cancer in men after skin
cancer. The American Cancer Society (ACS) estimate that the U.S. will see
around 164,690 new cases of prostate cancer and 29,430 deaths to the disease in
2018.
Hormone therapy
for prostate cancer
Although
it can be serious, most men diagnosed with prostate cancer will not die of it.
This is why today in the U.S., there are 2.9 million men living with or who
have survived the disease.
In
general, prostate cancer survival rates are higher the earlier the cancer is
detected and treated. However, many other factors can also affect a man's
outlook, including how well his cancer reacts to treatment.
A
research project lasting 6 years has identified dozens of genes that could help
identify men at higher risk of prostate cancer.
The
male sex hormone androgen stimulates tumor growth in prostate cancer. Hormone
therapy — also known as androgen deprivation or androgen-targeting therapy —
aims to halt tumor growth by reducing androgen levels or by blocking its effect
on tumor cells.
The
treatment can be used, for example, to shrink tumors before radiation therapy,
or to treat men in whom surgery or radiation therapy has been ruled out.
Hormone
therapy can be successful, but there are cases when the tumor develops
resistance to the treatment and then comes back or spreads.
Transforms
cancer into more aggressive type
In
their study paper, the Cedars-Sinai researchers reveal that a possible reason
for this is that the hormone therapy triggers a fundamental change in the
tumor.
It
causes some cancer cells, which are mainly of the common adenocarcinoma type,
to transform into a much rarer type called neuroendocrine, which occurs in less
than 1 percent of cases.
"This
transformation is a problem," says senior study author Neil A. Bhowmick,
who is the co-director of the Cancer Biology Program at Cedars-Sinai,
"because neuroendocrine prostate cancer is especially aggressive,
metastasizes more readily, and is more resistant to both androgen-targeted
therapy and chemotherapy."
He
explains that there is evidence to suggest that around a quarter of men treated
with hormone therapy can experience a return of their cancer in which the
tumors look like neuroendocrine prostate cancer and become treatment resistant.
So,
working mainly with mice, he and his colleagues decided to focus on the
interaction between prostate cancer cells and their microenvironment inside the
tumor. The microenvironment is supported by cells called stromal cells.
The
team found that androgen deprivation therapy can influence genetic programs in
the stromal cells to cause prostate cancer to progress to "a more
aggressive differentiation state."
Rise in
glutamine
They
also observed that the cell transformation was accompanied by a rise in
glutamine, an amino acid that is known to hasten the growth of cancer.
The
glutamine was being produced in the genetically altered stromal cells and
"served as a source of energy" for the cancer cells, as well as
helping transform the adenocarcinoma cells into neuroendocrine ones.
Finally,
the scientists confirmed the glutamine finding in humans. In a small group of
men who had prostate cancer, they found that those whose cancer was resistant
to treatment had higher levels of glutamine in their blood than those whose
cancer responded to treatment.
They
suggest that this means that it should be possible to develop a simple blood
test to detect those prostate cancers that are not responding to hormone
therapy and perhaps even predict resistance.
"To our surprise, we found this type
of therapy further changed the cellular environment in a way that caused
adenocarcinoma cells in the prostate to transform into neuroendocrine
cancer-type cells."
--------------------------------------------------------------------------------------------------------------------------------------
Roswell Park Team Identifies Possible Cause of Resistance to Prostate Cancer Treatment
A
Roswell Park-led research team has linked the development of
castration-resistant prostate cancer and resistance to treatment to a lack of
androgen receptor expression in prostate cancer cells, identifying a new
therapeutic target.
BUFFALO, N.Y. (PRWEB)
September 06, 2018
A
collaborative research team has linked the development of castration-resistant
prostate cancer and resistance to treatment to a lack of androgen receptor (AR)
expression in prostate cancer cells, identifying a new therapeutic target for
one of the deadliest forms of cancer among men. Results of this research, which
was led by scientists at Roswell Park Comprehensive Cancer Center, were
published today in the journal Nature Communications.
Prostate
cancer is one of the most common and treatable types of cancer in men. Most
patients respond well to hormone therapy or chemotherapy, and five-year
survival rates have reached nearly 100% thanks to advances in detection and
treatment. However, prostate cancer remains the second-leading cause of male
cancer deaths, because those with more advanced or aggressive forms of the
disease eventually experience progression or recurrence despite treatment.
For
men with advanced disease and tumors that cannot be surgically removed,
standard therapy involves drugs that target and block AR, a protein that binds
to androgens (male hormones). AR-targeted therapies stop or inhibit the growth
of prostate cancer cells, but for unknown reasons, their effectiveness is
usually short-lived. Within a year or two of antiandrogen therapy, many
patients will develop castration-resistant prostate cancer, an aggressive and
treatment-resistant form of the disease.
In
an effort to uncover the mechanisms of treatment resistance and progression in
prostate cancer, a team of scientists led by Dean Tang, PhD, Chair of
Pharmacology and Therapeutics at Roswell Park Comprehensive Cancer Center, in
collaboration with scientists at other cancer centers and research institutions
in the United States and China, examined AR expression patterns in 89 patients
with castration-resistant prostate cancer and found three distinct types: AR in
the nucleus of the cancer cell, AR in both the nucleus and cytoplasm, and near
or complete absence of AR from all parts of the cell.
Further
research confirmed that cells lacking AR did not respond to treatment with
enzalutamide (brand name Xtandi), an AR blocker commonly used to treat patients
with castration-resistant prostate cancer. These prostate cancer cells were
also more likely than AR-containing cells to grow, regenerate and proliferate.
Through deep RNA-Seq analysis, the team identified BCL-2, a stem-cell-enriched
prosurvival molecule, as a critical regulator and important therapeutic target
in castration-resistant prostate cancer cells.
“In
order to survive the pressure of chemical castration and antiandrogen therapy,
prostate cancer cells overexpress, redistribute or lose androgen receptor,”
explains Dr. Tang, the senior author of the study. “Our study offers new
proof-of-principle therapeutic strategies to not only treat advanced and
metastatic prostate cancer but also prevent castration resistance.”
The
research team also reports new evidence that combination treatment with
enzalutamide and ABT-199 (brand name Venetoclax), a newly FDA-approved BCL-2
inhibitor, markedly inhibits experimental castrate-resistant prostate cancer.
Dr. Tang has initiated a phase Ib/II clinical trial based on these findings, in
collaboration three Roswell Park clinical colleagues: Gurkamal Chatta, MD,
James Mohler, MD, and Igor Puzanov, MD, MSCI, FACP, who are also co-authors on
the new published research.
The
study, “Linking prostate cancer cell AR heterogeneity to distinct castration
and enzalutamide responses,” is available at
https://www.nature.com/articles/s41467-018-06067-7. This research was supported
by grants from the National Cancer Institute (project numbers R01CA155693,
P30CA016056 and P01CA77739) and the U.S. Department of Defense
(W81XWH-13-1-0352, W81XWH-14-1-0575 and W81XWH-16-1- 0575), as well as the
Cancer Prevention Research Institute of Texas, Chinese Ministry of Science and
Technology and National Natural Science Foundation of China.
For
an online version of this release, please visit:
https://www.roswellpark.org/media/news/roswell-park-team-identifies-possible-cause-resistance-prostate-cancer-treatment
Roswell
Park Comprehensive Cancer Center is a community united by the drive to
eliminate cancer’s grip on humanity by unlocking its secrets through
personalized approaches and unleashing the healing power of hope. Founded by
Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated
comprehensive cancer center in Upstate New York. Learn more at
http://www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or ASKRoswell@roswellpark.org.
--------------------------------------------------------------------------------------------------------------------------------------
Is regular screening for prostate cancer really necessary?
Published
Friday 7 September 2018
By
Maria Cohut
Fact
checked by Jasmin Collier
A
BMJ commission considered whether or not regular screening for prostate cancer
using the prostate-specific antigen test is truly necessary, despite the
possible risks it carries.
PSA
test sample
Should
men opt for routine screening for prostate cancer?
According
to an official statement released by the United States Preventive Services Task
Force in JAMA, men in the U.S. face an 11 percent lifetime risk of being diagnosed
with prostate cancer and a lifetime risk of prostate cancer-related death of
2.5 percent.
Previous
studies suggested that one effective way of catching this type of cancer early
is screening.
This
involves prostate-specific antigen (PSA) testing, which is a blood test that
can help establish a diagnosis.
However,
PSA testing is not always accurate and might lead to the prescription of
unnecessary — and invasive — biopsies, which may harm a person's quality of
life.
False
positive PSA results can also result in overdiagnosis and overtreatment, which
may affect a person both mentally and physically, thus impacting their overall
health.
So,
a commission of international experts — both clinicians and research
methodologists — and men at high risk of prostate cancer has reviewed and
analyzed the results of existing studies weighing up the benefits and risks
involved in routine prostate cancer screening.
The
results of this complex analysis are now reported in The BMJ.
More
harm than good?
The
panel analyzed data collected from 721,718 men enrolled in various trials, and
it assessed the evidence that emerged from these studies.
Following
a detailed analysis, the members of the panel concluded that routine screening
for prostate cancer should not be recommended to most men as it may end up
doing them more harm than good.
New
technique treats prostate cancer in just five radiotherapy sessions
New
technique treats prostate cancer in just five radiotherapy sessions
Have
researchers finally found a quick way to treat prostate cancer?
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now
"Based
on moderate- and low-quality evidence, PSA screening seems to increase the
detection of prostate cancer of any stage, increases the detection of stage 1
and 2 prostate cancer, and slightly decreases the detection of stage 3 and 4
prostate cancer," write the review's authors.
"Meanwhile,"
they add, "PSA screening is associated with considerable biopsy-related
and cancer treatment-related complications."
"We estimated that, for every 1,000
men screened, approximately one, three, and 25 more men will be hospitalised
for sepsis, require pads for urinary incontinence, and report erectile
dysfunction, respectively."
At
the same time, however, the experts involved in the review note that men who
qualify as being at high risk of prostate cancer may still want to consider
regular testing after discussing all the possible risks and benefits with their
doctors.
Men
who are at high risk of prostate cancer, according to guidelines from the
Centers for Disease Control and Prevention (CDC), are usually those who have a
family history of prostate cancer, as well as those of African descent.
The
BMJ panel also says that practicing doctors should not feel like they have to
suggest prostate cancer screening to all their male patients, but they should
aim to inform those who do wish to undertake PSA testing, assisting them in
their decision-making process.
In
an editorial written by Prof. Martin Roland and team, from the University of
Cambridge in the United Kingdom, other specialists support the conclusions
reached by the panel.
The
editorial's authors suggest that, when speaking with patients considering a PSA
test, clinicians "should explore their reasons for requesting a test, and
include evidence-based discussions about possible harms and benefits of PSA
testing, informed by the patient's ethnicity and family history."
--------------------------------------------------------------------------------------------------------------------------------------
NCI Expert Stresses Importance of Multimodal Imaging in Prostate Cancer
Brandon
Scalea
Peter
L. Choyke, MD, FACP
Multimodality
imaging holds the keys to providing personalized therapy to patients with
prostate cancer, said Peter L. Choyke, MD, FACP.
Each
screening platform has pros and cons, but their limitations can be erased with
a combined effort, added Choyke, who is director of the Molecular Imaging
Program and head of the Imaging Section at the National Cancer Institute (NCI).
For
example, an MRI gives a standard anatomical overview of a tumor but is not
specific enough, he said. A PET scan offers more specificity but lacks in terms
of anatomy. In combination, however, these 2 options have a greater benefit.
“It
is really about getting a more complete picture about where a patient stands in
their disease’s natural history,” Choyke said.
Additional
imaging methods have helped evolve this area in prostate cancer, including MRI
ultrasound fusion-targeted biopsy and PSMA-PET.
In
an interview with OncLive®, Choyke discussed the clinical implications of
emerging technologies for prostate cancer imaging.
OncLive:
What newer technologies are you excited about?
Choyke:
Our team at the NCI developed a method of fusing MR images with ultrasound images
so that we could do fusion biopsies of prostate cancer. It has really taken
off. There are now a lot of people doing it, and we are really gratified by
that. That is a fusion of MRI and ultrasound. We then moved on to looking at
PET scans, particularly one that targets prostate-specific membrane antigen
(PSMA), which is found in more aggressive cases of prostate cancer. It is very
specific.
We
are finding out a lot of new things about prostate cancer because this is a
changing picture of the disease. We are combining some of the traditional PET
imaging like 18F-sodium fluoride bone scans with PSMA. We are finding some
interesting things there. It is combining different methods together to figure
out what's going on and guide management of patients.
What
is the rationale for combining these technologies?
There
was this widespread idea that doctors were either just MRI specialists or they
were PET specialists. Now, we view it as whatever the best tool is to handle
that particular problem is the way to go. For example, I started out as an MRI
specialist, but I quickly realized there were limitations to what an MRI can
do. Particularly, an MRI lacks specificity. We could see lesions, but we could
not see whether they were cancerous or not. PET offers specificity, but the
anatomy is not that good. You get the anatomy from the MRI and the sensitivity
from the PET, and those 2 things go together very nicely.
We
want to more accurately say, "This is where you are now, and this is the
best therapy." We want to match the right diagnosis with the right
therapy.
What
is the importance of a multimodality approach, specifically in prostate cancer?
It
is very important. One of the things we are finding is that the disease goes
over multiple disciplines. You have to bring all kinds of different management
strategies to the table at different points in the disease. Depending on what
the imaging shows, you can bring in different specialists. It is very important
to have everybody at the table because the old way is for a patient to see 1
specialist. If the imaging or clinical parameters point in a different
direction, you would want an additional specialist. The way to address that is
a multidisciplinary approach so everybody sees everything, and you can decide
on the best direction. We have done this at the NCI.
What
other research would you like to highlight?
We
are comparing 2 different kinds of PET scans. We are looking at PSMA scans and
18F-sodium fluoride PET scans, which is a type of bone scan. We are finding
that they do not completely match up with each other. Early on in the disease,
they match up better. However, as the disease progresses, you get progressively
less matching up. This is important because some therapies are very dependent
on the bone turnovers. This is reflected by sodium fluoride.
We
are finding that PSMA-PET scans, which indicates where the active disease is,
sometimes does not overlap with the sodium fluoride. You can administer an
agent like radium-223 dichloride (Xofigo), but it will not treat the cancer. We
are learning about how to get smarter with selecting patients for radium-223 to
make sure the right patient gets the right therapy.
PSMA-PET
scan can be linked to a therapeutic radioisotope. It is very exciting to be
able to put a therapy on the PSMA, so it will go to the lesion and treat it
using targeted radionuclides. It is already in Europe and has had some dramatic
responses. Some were even complete responses. We are very eager to go in that
direction at NCI, and we have some planned studies coming up.
--------------------------------------------------------------------------------------------------------------------------------------
IL‐23 promotes the development of castration‐resistant prostate cancer
Juming
Yan
Daniel
J Cua
Michele
WL Teng
First
published: 08 September 2018
https://doi.org/10.1111/imcb.12195
Androgen‐deprivation
therapy is standard‐of‐care for
prostate cancer (PCa). Although nearly all patients respond to treatment, most
will eventually progress to a fatal stage of the disease, termed castration‐resistant
prostate cancer (CRPC).1 While deregulation of androgen receptor (AR)
signalling in PCa is a known mechanism of resistance to androgen‐deprivation
therapy,1 whether immune cells also contribute to the emergence of CRPC is
unclear. Now Calcinotto et al. has reported that androgen deprivation promotes
invasion of IL‐23‐producing
myeloid‐derived‐suppressor cells
(MDSCs) into the tumor microenvironment (TME) (Figure 1). Remarkably, IL‐23
can directly activate the AR signalling pathway in prostate tumor cells to
promote their survival and proliferation.2
MDSCs
have been shown to infiltrate the TME of many human cancer types, including
PCa, and can be categorized into two subgroups, monocytic MDSCs or
polymorphonuclear (PMN)‐MDSCs.2 Using multiplex
immunofluorescence, the authors reported that PMN‐MDSCs were
selectively enriched in human biopsies of CRPC compared to CSPC, and the PMN‐MDSCs
were localized in close proximity to tumor cells.2 Pre‐clinically,
the Pten‐null prostate conditional knockout mouse
model (PtenPC−/−) develops
castrate‐sensitive prostate cancer (CSPC), which
progresses to CRPC following surgical castration, and this mimics the disease
progression observed in humans.3 Using this model, the authors demonstrated
that surgical castration of these mice led to initial tumor regression followed
by progression and emergence of CRPC. Similar to their observation in human
CRPC biopsies, castration led to a selective increase of PMN‐MDSCs
in the prostate of the PtenPC−/− mice and this
coincided with the emergence of CRPC. This increase in PMN‐MDSCs
was also observed in castrated mice harbouring subcutaneous androgen‐dependent
mouse PCa cell lines, TRAMP‐C1 and MyC‐CaP.
Figure 1
IL‐23
promotes the development of castration‐resistant
prostate cancer. Androgen‐deprivation therapy promotes the
infiltration IL‐23‐producing
myeloid‐derived‐suppressor cells
(MDSCs) to the tumor microenvironment (TME) where it directly activates the
androgen receptor (AR) signalling pathway in prostate tumor cells (PC) to
promote their survival and proliferation.
The
authors hypothesized that factors produced by tumor infiltrating PMN‐MDSCs
may directly contribute to the development of CRPC. They first generated
conditioned media using either human or mouse bone‐marrow
derived MDSCs and showed that the media contained a growth factor that promoted
AR gene activation even when the cells were grown in fully androgen‐deprived
media. This suggests that a myeloid cell‐derived factor
is able to replace androgen to fuel PCa tumor survival and growth. By comparing
tumors from castrated PtenPC−/−mice to
controls, the authors observed significant upregulation of the genes encoding
pro‐inflammatory IL‐23
and IL23R as well as the chemokine receptor/ligand pair CXCR2 and CXCL5, which
are required for the recruitment of MDSCs. Using flow cytometry, the authors
also showed that PMN‐MDSCs from tumors of castrated PtenPC−/−mice expressed
higher levels of IL‐23p19, a subunit of IL‐23.
However, it appears that PMN‐MDSCs from WT
control mice do express surprisingly large amounts of IL‐23p19.
IL‐23 is a hetero‐dimeric
cytokine comprising the IL23p19 and IL‐12p40 subunits
and can only be secreted when both subunits are produced by the same cell.
Although the authors showed that in vitro stimulated BM‐MDSCs
secreted IL‐23, it remained unclear whether the
circulating IL‐23 was actually produced by PMN‐MDSCs
in the castrated versus control PtenPC−/−mice. In humans, plasma levels of IL‐23
were significantly higher in CRPC compared to CSPC although in general their
levels were low and its basal level in healthy volunteers was not examined.
Importantly, IL23R was up‐regulated in the prostate tumors of
castrated PtenPC−/−mice, although
tumors from sham‐castrated PtenPC−/− mice already
expressed high levels of IL23R. This was interesting as mouse tumor cell lines
are generally thought to not express IL23R. In contrast, IL‐23R
expression on human tumor cell lines such as lung adenocarcinoma, oral squamous
cell carcinoma and colon carcinoma has been reported, where its engagement
generally increased proliferation and invasive capability depending on the
concentration of IL‐23.4 Although androgen‐deprivation
therapy can directly suppress PCa growth, it is also known to increase the
infiltration of lymphoid and myeloid immune cells into the TME early post‐castration,
which diminishes as castration resistance emerges.5 Potentially this
inflammatory infiltration may suppress PCa growth initially, but over time with
the increase in IL‐23, this inflammatory reaction may
sculpt the tumor and its TME to promote its growth and escape in the process of
cancer immunoediting.6 The balance of IL‐12–IL‐23
axis has previously been shown to have an important role in controlling the
equilibrium phase of cancer immunoediting, which has been best characterized in
an MCA carcinogen‐induced mouse fibrosarcoma model.7 IL‐23
has also been shown to promote tumor initiation, growth and metastases in
experimental and de novo mouse models of cancer by indirectly suppressing T and
NK cell effector function.7
Overall,
androgen deprivation results in mobilization and recruitment of IL‐23‐producing
PMN‐MDSCs to the PCa TME and enhances PCa
expression of IL‐23R and subsequent activation of STAT3
and RORγ transcription
factors.8, 9 RORγ then recruits
transcription coactivators, SRC‐1 and SRC‐3
to the ROR response elements (RORE) within the AR‐RORγ target gene clusters.9 Therefore, IL‐23
activation of RORγ is an “alternate
survival pathway” that can replace AR‐dependent
signalling. Next, the authors showed that androgen‐deprived
PCa cells from PtenPC−/−x Il23a−/− mice that could
not produce IL‐23, had reduced levels of STAT3 and RORγ, consistent with the premise that IL‐23R
activation on PCa cells maintained their proliferation and survival. The
importance of MDSCs in promoting CRPC was also shown, where a CXCR2 antagonist
reduced infiltration of PMN‐MDSCs into the
tumors of castrated PtenPC−/− mice or TRAMP‐C1,
MyC‐CaP tumor‐bearing mice. By
inhibiting PMN‐MDSCs, AR proliferative genes were
suppressed and tumor growth was reduced in all three models. To support the
therapeutic relevance of their findings, castrated PtenPC−/− mice were
treated with anti‐IL‐23p19 and AR
antagonist enzalutamide either alone or in combination in mice that started to
develop CRPC. Strikingly, the combination therapy was highly effective in
reversing PCa resistance to castration as a greater proportion of mice had
normal‐appearing prostate glands and decreased
prostate volume after 5 weeks of treatment.
The
demonstration that androgen deprivation may upregulate IL23R on PCa, suggests
an unappreciated link between sex hormones and IL‐23R expression
on “non‐immune”
somatic cells. Going forward, it will be interesting to determine whether this
is limited to androgens, or whether estrogen deprivation similarly upregulates
IL‐23R in estrogen receptor positive breast
and ovarian cancer. Somatic cells of epithelial origin from various organs such
as liver, kidney and gastrointestinal tract can express IL‐23R
(https://www.proteinatlas.org/ENSG00000162594-IL23R/tissue) and may have the
potential to further upregulate IL‐23R under
pathological conditions; this should now be investigated. Indeed, there are
multiple colorectal cancer‐derived cell
lines that express high levels of IL‐23R (Dan Cua,
personal observation). Given that neutralizing antibodies to IL‐23
are clinically available and safe, it will be interesting to evaluate their use
in combination with enzalutamide to treat men with CRPC. We recently reported
that blocking IL‐23R may be more effective than
neutralizing IL‐23 ligand in the suppression of tumor
metastases.10 Given the direct effects of IL‐23R on driving
the emergence of CRPC, and the availability of experimental anti‐human
IL‐23R neutralizing antibodies,11 it will
be of interest to determine whether anti‐IL‐23R
in combination with enzalutamide may be an even more effective combination than
anti‐IL‐23p19 plus
enzalutamide for the treatment of CRPC.
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