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Study Finds that Both Women and their Primary Care Physicians Confusion over Ovarian Cancer Symptoms May Lead to Misdiagnosis

Reporter: Stephen J. Williams, Ph.D.

This post discusses the recently released “The Every Woman Study” conducted by the World Ovarian Cancer Coalition.  For full PDF of the study please click here: WOCC-Every-Woman-Study-Summary-Report-Oct-16

The findings are summarized nicely in the NPR article from Joanne Silberner below but just want to list a few takeaways from the study

  1.  Ovarian Cancer, while not the most common cancer in women, is still one of the most deadly malignancies.  A major reason for this is the inability to catch the disease in its early, and most treatable stages.  Much work is being done on early detection (a few posts on this area from this online journal are given at the end of this post for reference)
  2. The symptoms of ovarian cancer closely mimic symptoms of gastrointestinal distress and disorders and many times these symptoms are overlooked by women as benign, temporary issues and may be mis-self diagnosed.  In addition, if mistaken for common gastrointestinal discomfort or gynecologic discomfort (cramping)  women may self-medicate with over the counter agents which mask the symptoms of ovarian cancer
  3. certain lessons can be learned from the experiences in other countries regarding access to healthcare and diagnosis. For instance

Looking at the key findings of the study it becomes clear that countries have significant potential to
learn from each other:
• Women in Germany had the shortest time to diagnosis, but much less access to
specialist clinicians that are key to successful treatment.
• Women in the UK have almost universal access to specialists but the lowest
proportion of women diagnosed within a month of visiting a doctor.
• Women in Japan had one of the shortest times to diagnosis, but very little access to
genetic testing, and were least likely to get the emotional support they needed.
• Women in the USA were most likely to wait more than three months before
consulting a doctor about symptoms, but most likely to receive genetic testing.
• Women with ovarian cancer in Hungary were most aware of ovarian cancer before
their diagnosis, but were much less likely to be offered surgery to treat their disease.

 

In summary it appears there are three key areas needing to be addressed with regard to improving early reporting of symptoms of ovarian cancer

  1. information and awareness of symptoms by BOTH women and their physicians
  2. family risk assessment programs are very important to make women aware of their risks and needs for screening
  3. access to specialist treatment is important in the early diagnosis and treatment of this disease

 

Learn the Symptoms

Symptoms (from the Sandy Rollman Ovarian Cancer Foundation)

Historically ovarian cancer was called the “silent killer” because symptoms were not thought to develop until the chance of cure was poor. However, recent studies have shown this term is untrue and that the following symptoms are much more likely to occur in women with ovarian cancer than women in the general population. These symptoms include:

  • Bloating
  • Pelvic or abdominal pain
  • Difficulty eating or feeling full quickly
  • Urinary symptoms (urgency or frequency)

Women with ovarian cancer report that symptoms are persistent and represent a change from normal for their bodies. The frequency and/or number of such symptoms are key factors in the diagnosis of ovarian cancer. Several studies show that even early stage ovarian cancer can produce these symptoms.

Women who have these symptoms almost daily for more than a few weeks should see their doctor, preferably a gynecologist. Prompt medical evaluation may lead to detection at the earliest possible stage of the disease. Early stage diagnosis is associated with an improved prognosis.

Several other symptoms have been commonly reported by women with ovarian cancer. These symptoms include fatigue, indigestion, back pain, pain with intercourse, constipation and menstrual irregularities. However, these other symptoms are not as useful in identifying ovarian cancer because they are also found in equal frequency in women in the general population who do not have ovarian cancer.

 

In addition there are serum biomarker tests which have shown useful in the screening for ovarian cancer however these tests have their caveats and not generally suggested for whole population screening due to number of false postitives which may occur (these tests will be discussed in further posts)

Serum biomarker tests include:

 Taken From NPR at https://www.npr.org/sections/goatsandsoda/2018/10/21/658798956/report-women-everywhere-dont-know-enough-about-ovarian-cancer

Report: Women Everywhere Don’t Know Enough About Ovarian Cancer

Colored scanning electron micrograph of dividing ovarian cancer cells.

Steve Gschmeissner/Science Source

new study of women with ovarian cancer shows that ignorance about the condition is common among patients in all 44 countries surveyed. And that ignorance has a cost. The disease is more treatable, even potentially curable, in its early stages.

The women’s answers also suggested their doctors were ignorant. Many of them reported that diagnosis took a long time and that they weren’t referred to proper specialists.

The study was based on an online survey of 1,531 women who had been diagnosed with the cancer and was conducted by the World Ovarian Cancer Coalition, a nonprofit support group between March and May of this year.

Ovarian cancer is the eighth leading cause of cancer in women, according to the World Health Organization. Nearly 300,000 women will develop it this year. The World Ovarian Cancer Coalition estimates that one in six will die within three months of diagnosis and fewer than half will be alive in five years.

Prior to their diagnosis, two-thirds of the women surveyed either had never heard of ovarian cancer or were familiar with the name but didn’t know anything about the disease.

 

Other articles related to Ovarian Cancer on this online Open Access Journal Include:

Model mimicking clinical profile of patients with ovarian cancer @ Yale School of Medicine

New Findings in Endometrial Cancer: Mutations, Molecular Types and Immune Responses Evoked by Mutation-prone Endometrial, Ovarian Cancer Subtypes

Good and Bad News Reported for Ovarian Cancer Therapy

Efficacy of Ovariectomy in Presence of BRCA1 vs BRCA2 and the Risk for Ovarian Cancer

Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test

Ultrasound-based Screening for Ovarian Cancer

Warning signs may lead to better early detection of ovarian cancer

Epigenetics, Environment and Cancer: Articles of Note @PharmaceuticalIntelligence.com

Early Diagnosis [Early Detection Research Networks]

 

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Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

Curator: Stephen J. Williams, PhD 

Below is a series of posts and articles related to the role of G protein coupled receptors (GPCR) in various chronic diseases.  This is only a cursory collection and by no means represents the complete extensive literature on pathogenesis related to G protein function or alteration thereof.  However it is important to note that, although we think of G protein signaling as rather short lived, quick, their chronic activation may lead to progression of various disease. As to whether disease onset, via GPCR, is a result of sustained signal, loss of desensitization mechanisms, or alterations of transduction systems is an area to be investigated.

From:

Molecular Pathogenesis of Progressive Lung Diseases

Author: Larry H. Bernstein, MD, FCAP

 

Chronic Obstructive Lung Disease (COPD)

Inflammatory and infectious factors are present in diseased airways that interact with G-protein coupled receptors (GPCRs), such as purinergic receptors and bradykinin (BK) receptors, to stimulate phospholipase C [PLC]. This is followed by the activation of inositol 1,4,5-trisphosphate (IP3)-dependent activation of IP3 channel receptors in the ER, which results in channel opening and release of stored Ca2+ into the cytoplasm. When ER Ca2+ stores are depleted a pathway for Ca2+ influx across the plasma membrane is activated. This has been referred to as “capacitative Ca2+ entry”, and “store-operated calcium entry” (3). In the next step PLC mediated Ca2+ i is mobilized as a result of GPCR activation by inflammatory mediators, which triggers cytokine production by Ca2+ i-dependent activation of the transcription factor nuclear factor kB (NF-kB) in airway epithelia.

 

 

 

In Alzheimer’s Disease

Important Lead in Alzheimer’s Disease Model

Larry H. Bernstein, MD, FCAP, Curator discusses findings from a research team at University of California at San Diego (UCSD) which the neuropeptide hormone corticotropin-releasing factor (CRF) as having an important role in the etiology of Alzheimer’s Disease (AD). CRF activates the CRF receptor (a G stimulatory receptor).  It was found inhibition of the CRF receptor prevented cognitive impairment in a mouse model of AD.  Furthermore researchers at the Flanders Interuniversity Institute for Biotechnology found the loss of a protein called G protein-coupled receptor 3 (GPR3) may lower the amyloid plaque aggregation, resulting in improved cognitive function.  Additionally inhibition of several G-protein coupled receptors alter amyloid precursor processing, providing a further mechanism of the role of GPCR in AD (see references in The role of G protein-coupled receptors in the pathology of Alzheimer’s disease by Amantha Thathiah and Bart De Strooper Nature Reviews Feb 2011; 12: 73-87 and read post).

 

In Cardiovascular and Thrombotic Disease

 

Adenosine Receptor Agonist Increases Plasma Homocysteine

 

and read related articles in curation on effects of hormones on the cardiovascular system at

Action of Hormones on the Circulation

 

In Cancer

A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial

 

Further curations and references of G proteins and chronic disease can be found at the Open Access journal https://pharmaceuticalintelligence.com using the search terms “GCPR” and “disease” in the Search box in the upper right of the home page.

 

 

 

 

 

 

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Almudena’s Story:  A Life of Hope, Rejuvenation and Strength

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

Patient had ovarian clear cell adenocarcinomas (OCCAs) and underwent a complete hysterectomy at age 52. Interview was conducted 15 months’ post-surgery. Earlier in life, patient had thyroid cancer and removal of her thyroid gland and all the lymph nodes in her neck.

 

Almudena Seeder-Alonso, originally from Madrid, Spain, and now living in Amsterdam, The Netherlands, with her Dutch husband, René, is the eternal optimist, embracing life, reinventing herself, and looking for opportunity in every moment. She is an influential blogger of international relations issues, a career professional in human resources management in both corporate and consulting businesses in Legal, Accounting and Technology, and a lawyer and political scientist with an advanced degree in international relations who is also pursuing a Ph.D. in international relations and diplomacy. And she speaks four languages fluently – Spanish, Dutch, Portuguese and English.

Her story is one of hope, rejuvenation and strength that defines her effervescent personality. One year ago, a routine gynecology exam changed her outlook and perspective on life. She would have never thought that her diagnosis would be ovarian carcinoma of the clear cell, the most aggressive form of cancer.

 

Image SOURCE: Photographs courtesy of Almudena Seeder-Alonso. Top Left: Almudena’s parents, María and Angel, and sister, Cristina, and her husband. Top Right: Almudena during chemotherapy last summer (2015). Middle: Almudena attending a wedding in Asturias (northwest Spain – May 2016), Almudena and René in Comporta, Portugal (Summer 2014) and in New York (April 2014). Below left: Almudena in New York (April 2014). Below Right: Almudena’s sisters, María and Cristina with nephew, Jaime (May 2016). 

A Small Cyst Turns Into Diagnosis of Ovarian Cancer

In early 2015, Almudena visited her gynecologist in Amsterdam for a regular, yearly appointment.

“I was feeling fine. I had no physical complaints, except for my monthly periods which were heavy. I didn’t think much about it. During my examination, my doctor told me that she found a small cyst on my right ovary and we would just observe it to make sure it was not growing.”

Almudena went back to her gynecologist at the OLVG (Onze Lieve Vrouw Gasthuis https://www.olvg.nl/) in Amsterdam twice over the next month to monitor the cyst, only to find that the cyst was growing slightly. Her gynecologist recommended blood tests, an ultrasound, and a specimen of the cyst to be removed through a laparoscopy, a procedure requiring small incisions made below the navel using specialized tools.

“The pathology report said that the cyst was an aggressive cancer, called ovarian carcinoma of the clear cell. I remember sitting in my doctor’s office once she told me the results of the test, and I got very quiet. I could not believe that this was happening to me. While I was meeting with the doctor, I called my husband to let the doctor inform him about the situation. I was listening to this conversation but from far away. He immediately left his meeting with his client (he is one of two founding partners of SeederdeBoer, a Dutch Consulting & Technology firm), to come home. I left the doctor’s office, went home and cried in my husband’s arms.”

Almudena then called her parents, María and Angel, and her two sisters, María and Cristina who live in Madrid, to tell them the news.

“My Mother was very emotional when she heard about my diagnosis. My Father, who is a quiet man by nature, asked me, ‘How could this be happening to you again?’ I did not have an answer for him.”

Almudena’s father was referring to his daughter’s diagnosis of thyroid cancer in her late 20s.

Diagnosis of Thyroid Cancer As A Young Woman

When Almudena was 27 years old, she was diagnosed with follicular thyroid cancer, a slow-growing, highly treatable type of cancer that forms in follicular cells in the thyroid gland. After a 12-hour surgery to remove the gland through a procedure called a full thyroidectomy, she also needed radiation therapy. Many years later, she is feeling fine and continues to be on thyroid medication for the rest of her life.

“I was not aware at that young age of the scope of the diagnosis, but my life really changed. I was kind of a party animal at the end of the 1980s, and I did not have any amount of energy for that anymore. I needed several months to get back into shape as the scar from the surgery was a large one on the right side of my neck. I could not use my right arm and hand properly for months, even writing was complicated. The worst news came later when I could not get pregnant given the situation that many of my eggs were gone because of radiation. At that moment, egg freezing technology was not as advanced as it is today; it was not normal to freeze eggs for a later time. That was really painful, as I could not become a mother, even after four in vitro fertilization (IVF) cycles.”

According to the National Cancer Institute’s web site, thyroid cancer is a disease in which malignant cancer cells form in the tissues of the thyroid gland. The thyroid is a gland at the base of the throat near the trachea (windpipe). It is shaped like a butterfly, with a right lobe and a left lobe. The isthmus, a thin piece of tissue, connects the two lobes. A healthy thyroid is a little larger than a quarter coin. It usually cannot be felt through the skin. The thyroid uses iodine, a mineral found in some foods and in iodized salt, to help make several hormones. Thyroid hormones control heart rate, body temperature, and how quickly food is changed into energy (metabolism) as well as, it controls the amount of calcium in the blood.  http://www.cancer.gov/types/thyroid/patient/thyroid-treatment-pdq

Ovarian Cancer Diagnosis Continues

Almudena then spoke with her physicians in Madrid, as that is where she grew up, to get a second opinion about her ovarian carcinoma diagnosis. The physicians knew her history well and they told her that they did not believe that the follicular thyroid cancer was directly related to the ovarian cancer.

“My local gynecologist in Amsterdam then referred me to a specialist, Dr. J. van der Velden, a gynecologist/oncologist at the Amsterdam Medisch Centrum (AMC), http://www.cgoa.nl/page/view/name/34-wie-we-zijn, one of the top university hospitals in The Netherlands for this surgery and treatment. My husband, René, and I met with Dr. van der Velden, and he told us that my cancer was a fast-spreading condition and I needed to have it removed immediately. He answered our questions, calmed my fears and said he would do everything to help me.

“I have an open attitude towards people so it was easy to create a good connection with the doctors and medical personnel, which I consider very fundamental in such a process. I talked to them about my concerns or doubts and shared my worries about the process that I was going through. I have to say that all of them were wonderful in every aspect!”

Dr. van der Velden explained to Almudena that as clear cell is an aggressive form of ovarian cancer, it would need to be treated that way. One month later, Almudena underwent a procedure called open surgery, rather than laparoscopic surgery, requiring an incision large enough for the doctor to see the cyst and surrounding tissue.

“My incision from the surgery is a constant reminder of the struggle I went through. The cyst, which was 3cm, was a solid mass on my right ovary. It had adhered itself to the ovary and had to be broken to be removed, so some cells spilled out into my reproductive organs, namely, in my uterus and fallopian tubes. During this surgery, which was a complete hysterectomy, the doctor took additional tissue samples of my reproductive organs to be analyzed by pathology. Weeks later, he found no other metastases or extra cancer cells.”

http://www.mountsinai.org/patient-care/health-library/treatments-and-procedures/ovarian-cyst-removal-open-surgery

https://www.amc.nl/web/Het-AMC/Organisatie/Academisch-Medisch-Centrum.htm

The Process of Healing Begins

One month later, Almudena’s body was still recovering from the operation. Now, she had to start chemotherapy back at the OLVG.

“The doctor, Dr. W. Terpstra, hematologist/oncologist instructed me that I would be going through six full cycles of chemotherapy, which means full doses of carboplatin & paclitaxel every 21 days. At first, I felt reasonably good, then as each week progressed, I became more and more tired, nauseous, and just feeling terrible. I was not sleeping well and even lost the sensation of my fingers and toes as chemo attacks the nerves, too. Then, I started losing my eyelashes and hair so I shaved my long, flowing hair and wore a scarf wrapped around my head.”

Almudena would report to the hospital for her weekly chemotherapy session, starting at 9am and leaving at 6pm. The medical team would put her in a room with a full-size bed so she can relax during the infusion. Her husband, two sisters and some close friends would take turns accompanying her during this time, as she had a nurturing and caring support network.

“I could not have gone through this condition without my family and friends. It tests your relationships and shows you who your friends really are.”

The chemotherapy affected Almudena’s red blood cell count halfway through the process and she felt weak and tired.

“Anemia is normal during this time, but always being tired made me concentrate and focus on things less. I would watch a movie or read a book through the chemo session, and then I would fall asleep quickly.”

After Almudena finished the complete cycle of chemotherapy infusions, she had a follow-up appointment with her doctor, which included blood work, CT scan, and other diagnostic tests.

“My doctor said the tests results were very good. Now, I see him every three months for a routine visit. That was such a wonderful report to hear.

“During this process I learned to love myself, and pampered myself and my body. I learned to improve in terms of beauty, even in the worst circumstances. I wanted to feel beautiful and attractive for myself and for my close family. After three chemo cycles, I started even to think about how my new hair style would be in the moment that I finished chemo.”

Ovarian Carcinoma Pathophysiology Facts

According to published studies, ovarian clear cell adenocarcinomas (OCCAs) account for less than 5 percent of all ovarian malignancies, and 3.7–12.1 percent of all epithelial ovarian carcinomas. By contrast, early‐stage clear cell ovarian cancer carries a relatively good prognosis. When compared with their serous counterparts, a greater proportion of OCCA tumors present as early‐stage (I–II) tumors, are often associated with a large pelvic mass, which may account for their earlier diagnosis, and rarely occur bilaterally. Very little is known about the pathobiology of OCCA. Between 5 percent and 10 percent of ovarian cancers are associated with endometriotic lesions in which there is a predominance of clear and endometrioid cell subtypes, suggesting that both tumor types may arise in endometriosis. http://www.cancer.gov/types/ovarian/hp/ovarian-epithelial-treatment-pdq

The National Cancer Institute’s web site offers these statistics. In most families affected with the breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage has been found to the BRCA1 locus on chromosome 17q21. BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12. The lifetime risk for developing ovarian cancer in patients harboring germline mutations in BRCA1 is substantially increased over that of the general population. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2001101/

Words Of Wisdom

“Throughout this journey, I found myself again in some way and found my strength as well. When it seemed I could not stand it anymore, either physically and mentally, I realized that I could.

“At the beginning of my diagnosis, I asked myself, ‘Why me?’, and I then changed it to, ‘Why not me?’ I discovered that I have the same opportunities as anyone who becomes ill. The important perspective to have is not whining and dwelling on my bad luck. The important thing is to heal, survive, and recover my life, which is very good!

“I learned the real value and importance of things: to differentiate and give real meaning and value to the care and support of my husband, René, who was always there for me, and my parents and sisters, who came to Amsterdam very often during the process. I also made sure that René was well-supported and accompanied by my family.  René was feeling terrible for me, but he never showed it — and I learned this fact after I was starting to be back on track.”

Almudena’s Life Today

“At a significant moment in my life during my cancer diagnosis and after a long professional life in many corporate and consulting business in several countries, I decided to re-invent myself and start a new career, this time, in the battle of the opinions. I always liked foreign affairs and diplomacy, so why not share my thoughts and write about current international issues.”

That’s when Almudena started a blog to discuss relevant international political issues with her background specialization in International Relations, International Politics, International Law and Governance.

“I consider myself politically liberal and have been influenced by J.S. Mill and A. Tocqueville’s tradition of thought, as well as their ethical conception of the defense of freedom. This is what I try to capture in my political approach and in this blog. http://almudenas.website/index.php/about-me/

“Regarding my profession, I have already reinvented myself, leaving the corporate life with all that is included regarding life’s standards, and do what really makes me happy, which I´m doing right now. It seems after all, looking back with perspective, I did the right thing.

“I am grateful for my life and never take anything for granted. I am the happiest when I am doing things that please me or give me the utmost satisfaction. I now have balance in my personal and professional life, something that I’ve never had before. My husband, René, likes it too and I have his full support.”

She recently ‘liked’ this saying on LinkedIn, the professional network site, ‘I never lose. I either win or learn,’ which was attributed to Nelson Mandela, the deceased South African anti-apartheid revolutionary, politician and philanthropist.

Almudena’s life continues on a path of balance, richness and thankfulness for the person she is and the many blessings she continues to have along the way.

Editor’s note:

We would like to thank Gabriela Contreras, a global communications consultant and patient advocate, for the tremendous help and support she provided in locating and scheduling time to talk with Almudena Seeder-Alonso.

Almudena Seeder-Alonso provided her permission to publish this interview on August 10, 2016.

REFERENCES/SOURCES

http://www.nytimes.com/2016/07/31/health/harnessing-the-immune-system-to-fight-cancer.html?_r=0

http://www.sharecancersupport.org/share-new/support/stories/linda_clear_cell_ovarian_cancer/

http://www.cancer.gov/types/thyroid/patient/thyroid-treatment-pdq

http://almudenas.website/index.php/about-me/

http://www.cancer.gov/types/ovarian/hp/ovarian-epithelial-treatment-pdq

http://www.cgoa.nl/page/view/name/34-wie-we-zijn

http://www.mountsinai.org/patient-care/health-library/treatments-and-procedures/ovarian-cyst-removal-open-surgery

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2001101/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2001101/

Other related articles on the link between Ovarian Cancer and Thyroid Cancer:

https://www.whatnext.com/questions/is-there-a-link-between-ovarian-and-thyroid-cancer

Other related articles/information:

https://www.olvg.nl/

https://www.amc.nl/web/Het-AMC/Organisatie/Academisch-Medisch-Centrum.htm

 

Other related articles on Ovarian Cancer and Thyroid Cancer were published in this Open Access Online Scientific Journal include the following: 

Ovarian Cancer (N = 285)

2015

A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial

Model mimicking clinical profile of patients with ovarian cancer @ Yale School of Medicine

https://pharmaceuticalintelligence.com/2015/09/26/model-mimicking-clinical-profile-of-patients-with-ovarian-cancer-yale-school-of-medicine/

2014

Preclinical study identifies ‘master’ proto-oncogene that regulates stress-induced ovarian cancer metastasis | MD Anderson Cancer Center

https://pharmaceuticalintelligence.com/2014/08/15/preclinical-study-identifies-master-proto-oncogene-that-regulates-stress-induced-ovarian-cancer-metastasis-md-anderson-cancer-center/

Good and Bad News Reported for Ovarian Cancer Therapy

https://pharmaceuticalintelligence.com/2014/07/01/good-and-bad-news-reported-for-ovarian-cancer-therapy-2/

Efficacy of Ovariectomy in Presence of BRCA1 vs BRCA2 and the Risk for Ovarian Cancer

https://pharmaceuticalintelligence.com/2014/02/25/efficacy-of-ovariectomy-in-presence-of-brca1-vs-brca2-and-the-risk-for-ovarian-cancer/

 

And 
 
Thyroid Cancer (N = 124)
2015
Experience with Thyroid Cancer

 

2012

Thyroid Cancer: The Evolution of Treatment Options

https://pharmaceuticalintelligence.com/2012/08/19/thyroid-cancer-the-evolution-of-treatment-options/

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Targeting PARP

Curator: Larry H. Bernstein, MD, FCAP

LPBI

 

 

Targeting PARP in Prostate Cancer: Novelty, Pitfalls, and Promise    
Review ArticleMay 15, 2016Oncology Journal, Prostate Cancer

http://www.cancernetwork.com/oncology-journal/targeting-parp-prostate-cancer-novelty-pitfalls-and-promise#sthash.fjYB5ROU.dpuf

 

http://www.cancernetwork.com/sites/default/files/styles/max_width/public/images/media/PARP-article-hero.jpg

© 2016 Steve Oh and Myriam Kirkman-Oh, KO Studios

Metastatic prostate cancer remains a highly lethal disease with no curative therapeutic options. A significant subset of patients with prostate cancer harbor either germline or somatic mutations in DNA repair enzyme genes such as BRCA1, BRCA2, or ATM. Emerging data suggest that drugs that target poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) enzymes may represent a novel and effective means of treating tumors with these DNA repair defects, including prostate cancers. Here we will review the molecular mechanism of action of PARP inhibitors and discuss how they target tumor cells with faulty DNA repair functions and transcriptional controls. We will review emerging data for the utility of PARP inhibition in the management of metastatic prostate cancer. Finally, we will place PARP inhibitors within the framework of precision medicine–based care of patients with prostate cancer.

Introduction
In 2016, prostate cancer is expected to be diagnosed in 180,890 men, and 26,120 will die of metastatic disease.[1] While the majority of localized prostate cancers can be controlled with surgery and/or radiation, metastatic disease remains a lethal disease with no curative options. Moreover, prostate cancer is a heterogeneous disease that can be highly lethal but also slow and indolent, as reflected by a 10-year estimated survival of 17% (S9346 trial, unpublished data). The advent of affordable and efficient techniques for profiling tumors molecularly represents an unprecedented opportunity to better characterize the molecular factors that result in indolent and/or lethal disease and to tailor therapy accordingly. Many clinical trials are already underway to examine whether molecularly targeted therapies can improve outcomes.[2] In this review, we will specifically examine the molecular rationale for one of these targeted approaches, poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibition, in prostate cancer. We will review how PARP inhibitors function as a class, review the molecular features that sensitize cancer cells to this therapy, and discuss the data supporting its potential for patients with prostate cancer. We will then outline a strategy for further development of PARP inhibitors in the prostate cancer field.
Metastatic prostate cancer is typically categorized as hormone-sensitive prostate cancer (HSPC), which responds to androgen ablation, or castration-resistant prostate cancer (CRPC), which develops resistance to gonadal suppression. Although bilateral orchiectomy is the historic gold-standard treatment for metastatic HSPC, gonadal suppression is currently accomplished with gonadotropin-releasing hormone agonists or antagonists with or without androgen receptor blockade. This approach remains the cornerstone of therapy for men with metastatic HSPC.[3] Emerging data from large phase III trials (CHAARTED and Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy [STAMPEDE]) have also revealed a large survival benefit for the combination of docetaxel and androgen deprivation in metastatic HSPC.[4,5]

Despite these initially effective treatments, the vast majority of men with metastatic HSPC will progress to CRPC, which is the lethal stage of the disease. For these patients, several additional therapies provide benefit by further suppression of androgen signaling (enzalutamide, abiraterone), disruption of the cell cycle in replicating cells (docetaxel, cabazitaxel), targeting of bone metastases (radium-223), or activation of antitumor immunologic response (sipuleucel-T).[6] While these therapies have undoubtedly extended the median survival of patients with metastatic CRPC, their impact on survival is modest and they clearly do not work for all men. In addition, we lack validated genomic markers that would allow better selection of patients for these therapies. Therefore, a better approach that leverages the individual and unique aspects of a patient’s cancer and utilizes therapy based on these factors may allow us to improve patient outcomes.

The development of high-throughput sequencing technology has made it feasible to comprehensively analyze the genetic mutations and gene expression changes in individual prostate cancers with a high degree of resolution in real time. Many institutions now routinely perform these analyses in the hope that they might uncover molecular features that predict response to certain therapies or provide guidance for clinical trial selection.[7] This approach, colloquially termed “precision” medicine, offers the potential promise of providing the right therapy for the right patient at the right time. In the context of prostate cancer, it means molecularly characterizing a tumor and then offering patients drugs that may specifically promote tumor lethality based on these molecular features. The limitation of this approach is that it requires that the target be truly biologically relevant and that there are drugs that can effectively target these molecular changes. The discovery of both somatic and germline DNA repair deficiencies in prostate cancer, together with the development of PARP inhibitors that can kill cancer cells with these defects, is a potent example of targeting therapy to molecularly defined tumor subtypes. While much early work validating this approach has occurred in breast and ovarian cancer populations, emerging data suggest that PARP inhibition is a potentially important strategy for managing a significant subset of prostate cancer patients.

 

PARP Inhibition: Targeting DNA Repair Deficiency

Molecular mechanism

PARP1 catalyzes the addition of poly(ADP)-ribose (PAR) groups to target proteins in a process termed PARylation.[8] PARP1 is part of a superfamily of proteins that consists of 18 members (including the related tankyrase enzymes), which have many functions within normal and cancer cells. PARP1, the founding member of this family, is responsible for the majority of PARylation of protein targets within cells. It is primarily present in the nucleus in association with chromatin, where it participates in DNA repair and regulation of gene expression by modulating protein localization and activity.[9]

DNA damage occurs continuously in all living cells as a result of oxidative damage or DNA replicative stress.[10] When DNA damage occurs on one strand of the DNA double helix, a single-strand break (SSB) results, but if two SSBs occur in close proximity and on opposite strands, the result is a double-strand break (DSB) and discontinuity of the chromosome (Figures 1 and 2). Even a single DSB is lethal to a human cell if unrepaired because of the risk of large-scale loss of genetic information.

PARP1 plays a critical role in restoration of genomic integrity by facilitating efficient repair of DNA SSBs and DSBs. PARP1 senses DNA damage by binding to the site of SSBs and DSBs and inducing auto-PARylation, which in turn promotes recruitment of DNA repair factors (such as DNA ligase III, polymerase β, and x-ray repair cross-complementing protein 1[XRCC1]).[11] Loss of PARP1 function by means of pharmacologic or genetic mechanisms results in impaired SSB repair and, following initiation of DNA replication, creation of a DNA DSB (see Figure 1). PARP may also play an important role in DSB repair and is known to recruit the MRE11-RAD50-NBS1 complex and to promote PARylation of BRCA1, factors required for the homologous recombination (HR) pathway of DNA DSB repair. Therefore, pharmacologic inhibition of PARP1/2 in DNA repair–defective (DRD) cells that lack efficient HR repair capabilities (such as those harboring BRCA1, BRCA2, or ATM mutations) results in failure to resolve SSBs, which are then converted to DSBs that promote cellular death.

The activity of PARP1 is not limited to DNA damage response. PARP1 is also known to regulate gene expression by modulation of transcription factor activity and regulation of chromatin.[12] PARP1 binds to RNA polymerase II, regulating gene expression, and may also affect tumor suppressor and oncogenic gene expression. PARP1 can also modulate hormone-dependent gene transcription from hormone-responsive nuclear receptors, such as estrogen receptors α and β, progesterone receptor, and androgen receptor.[9]

Furthermore, PARP1 can modulate the transcriptional activity of ETS transcription factors, which suggests that pharmacologic targeting of PARP1 may be useful in TMPRSS2:ERG fusion–positive prostate cancer cells (~50% of prostate cancers).[13] PARP1 physically interacts with the TMPRSS2:ERG gene fusion and the DNA–protein kinase complex, and these interactions are required for ERG-related gene transcription. Interestingly, PARP inhibition with olaparib inhibited prostate cancer xenograft growth if tumors harbored a TMPRSS2:ERG fusion, which suggests that PARP might represent a therapeutic option for prostate cancer patients withTMPRSS2:ERG fusions.[13] This concept is being evaluated in a recently completed clinical trial (National Cancer Institute [NCI] 9012).

PARP inhibitors

Given the biologic importance of PARP1 in the context of cancer, several pharmacologic agents that target this enzyme are currently under development (Table). Most PARP inhibitors mimic the NAD+ substrate of PARP1, competitively bind to the catalytic domain, and inhibit PAR synthesis.[14] PARP inhibitors require the expression of PARP1 and PARP2, and cells that lack expression of both genes are not sensitive to these agents. PARP inhibitors all appear to block catalytic activity and PAR synthesis in a roughly equivalent manner but may show differential ability to trap PARP1/2 at the site of DNA damage (niraparib > olaparib > veliparib), an event that blocks repair and promotes cellular lethality.[15,16] Whether these effects observed in vitro translate into clinically meaningful differences in efficacy is less clear. Furthermore, it is also now clear that the putative PARP inhibitor iniparib may not promote cytotoxicity via PARP inhibition. Several initial studies focused on iniparib, but when phase III trials failed to demonstrate the efficacy of this compound, additional mechanistic work demonstrated that iniparib may not truly be an effective PARP inhibitor.[17,18] These data illustrate the necessity of careful mechanistic characterization of any targeted agent prior to large-scale and expensive studies.

Germline DNA repair deficiency

Inherited defects in DNA repair pathways result in increased susceptibility to the development of malignancy.[19] Defects in mismatch repair proteins promote the development of tumors, including colon and uterine,[20] whereas inherited inactivating mutations in BRCA1 and BRCA2, which are required for efficient HR-based DNA DSB repair, significantly increase the risk of breast, ovarian, prostate, and other cancers.[21] Patients with these tumor types typically demonstrate homozygous inactivation of these genes, the first event occurring in the germline, with subsequent clonal somatic inactivation of the remaining allele.[21] These events presumably occur early in tumorigenesis and, by loss of robust DNA DSB repair, induce genomic instability, which causes loss of tumor suppressors, activation of oncogenes, and acceleration of tumorigenesis.

A germline mutation in BRCA1 or BRCA2 increases the risk of prostate cancer and thus may be found in 2% to 5% of prostate cancers.[22,23] The relative risk of development of prostate cancer for men ≤ age 65 with BRCA1 mutations is 1.8, but BRCA2 mutations in particular seem to increase the risk of prostate cancer formation by age 65 by about 8.6-fold. Mutations of BRCA1, BRCA2, and ATM (and perhaps other DNA repair genes) may also play a role in progression to the lethal castration-resistant state.[22,24-26] The frequency of BRCA2 germline mutations in prostate cancer alone may be as high as 2%.[22] Therefore, the development of therapies to target DNA repair is likely to benefit a relatively large and relatively young population.

Somatic DNA repair deficiency

In addition to germline defects, tumors can acquire defective DNA repair processes through somatic loss of DNA damage response genes, and these somatic mutations can also confer sensitivity to PARP inhibition.[27] This has led to the concept of “BRCAness,” which refers to somatically acquired defects in HR that, as a group, could predict tumor response to PARP inhibitors and cisplatin.[21] Somatic alterations can include either acquired mutations or epigenetic events that silence genes such as ATM; ATR; BRCA1 or –2; CHEK1 or -2; FANCA, -C, -D2, -E, -F; PALB2; MRE11 complex; or RAD51, which prevent efficient HR repair of DNA DSBs.

It is likely that a substantial proportion of men with prostate cancer may demonstrate aspects of BRCAness that could predict sensitivity to PARP inhibitors. Beltran et al performed targeted next-generation sequencing of tumors from men with advanced prostate cancer and found that 12% demonstrated BRCA2 loss and that 8% harbored ATM loss.[28] Furthermore, up to 19.3% of CRPCs demonstrate aberrations in BRCA1, BRCA2, or ATM; these events become more frequent as the disease progresses from hormone-sensitive to castration-resistant.[29] Together these data suggest that BRCAness is a reasonably frequent event in patients with advanced prostate cancer, which makes PARP inhibition an attractive target in this disease.

Synthetic lethality

The concept of promoting the killing of cancer cells by simultaneously blocking SSB repair using PARP inhibition in cells that lack efficient DSB repair is called “synthetic lethality.” In this scenario, tumor cells may harbor either germline or somatically acquired homozygous inactivation of HR. Germline defects (when present) typically affect only one allele in normal cells, and therefore normal tissues retain HR function. This difference between the DNA repair capacity of normal and cancer cells can be leveraged to produce selective cell killing of tumor cells by PARP inhibitors. Treatment of patients with PARP inhibitors will then block normal SSB repair in all cells, and these SSBs are subsequently converted to DSBs by DNA replication. In normal cells, HR restores the genome and allows survival, but in DRD cancer cells, DSBs persist, inducing cellular death selectively in the tumor cell population (see Figure 2).

http://www.cancernetwork.com/sites/default/files/styles/figures_diagrams/public/figures_diagrams/1605hussainFig2.png

Early-phase studies

Ample data indicate that PARP inhibitors possess antitumor activity within diverse patient populations, particularly those with BRCA1 or BRCA2 mutations.[14] One of the first studies to validate the concept of clinical benefit in patients with BRCA mutations was a phase I trial that looked at pharmacokinetic and pharmacodynamic aspects of olaparib treatment.[24] In this study, 60 patients with solid tumors were treated with various doses of olaparib (10 mg daily to 600 mg twice daily) to determine maximum tolerated dose (MTD). The study population was intentionally enriched for BRCA mutation carriers, and 22 patients of the cohort harbored BRCA1 or BRCA2 mutations. Objective tumor activity was observed in the mutation carrier population in patients with breast, ovarian, and prostate cancers. Three patients with advanced prostate cancer were included in this study cohort; the one with a BRCA2 mutation had a greater than 50% response in prostate-specific antigen (PSA) level, resolution of bone metastases, and an extended treatment course. This study suggested that there was a benefit of olaparib therapy in BRCA mutation carriers and the potential for benefit in prostate cancer patients. Further validation of olaparib efficacy in patients with BRCA mutations came from parallel proof-of-concept studies demonstrating the activity of this agent in women with breast and ovarian cancers and BRCA1 or BRCA2 mutations.[30,31] These data ultimately led to US Food and Drug Administration (FDA) approval of olaparib for women with a BRCA mutation and metastatic ovarian cancer after chemotherapy.
Additional data that demonstrate a similar spectrum of activity are available for other PARP inhibitors. Phase I data on the safety and pharmacodynamics of single-agent veliparib have been reported as an abstract,[32] and additional studies of veliparib in combination with mitomycin,[33] irinotecan,[34] and other agents have been reported.[35] VanderWeele et al published a case report of a patient with metastatic CRPC and BRCA2 mutation who had a sustained complete response to veliparib and carboplatin/gemcitabine.[36] It seems likely that many of the available PARP inhibitors may have overlapping activities, and further data will be needed to clarify which agent to use in which tumor type and the relative toxicities of each agent.

emozolomide and veliparib in metastatic CRPC

Compelling data implicate PARP1 in the mediation of DNA repair responses to alkylating agents,[37] cellular survival in BRCA-deficient cells,[24,38] and androgen receptor–mediated prostate cancer cellular proliferation.[9,39] Furthermore, data suggest that prostate cancers that harbor the TMPRSS2:ERG fusion (present in up to 50% of prostate cancers) may be more sensitive to PARP inhibition.[13] Therefore, Hussain et al carried out a single-arm pilot study to assess the safety and efficacy of veliparib with the alkylator temozolomide (TMZ) in patients with metastatic CRPC following docetaxel therapy.[40] In this study, patients with a PSA level of ≥ 2 ng/mL were treated with veliparib, 40 mg twice daily, on days 1 to 7 and TMZ, 150 to 200 mg/m2, on days 1 to 5 on a 28-day cycle, based on tolerance data from a phase I study (ClinicalTrials.gov identifier: NCT00526617). The primary endpoint was PSA response rate (30% decline). Of the 25 patients who were evaluable for response, 2 had a confirmed response, 13 had stable PSA, and 10 had progression. The most frequent toxicities were thrombocytopenia, anemia, fatigue, neutropenia, nausea, and constipation. The investigators did assess frequency of TMPRSS2:ERG fusion but found it in only one of eight evaluable patients. Although this patient had stable disease, no conclusions could be drawn regarding the contribution of the fusion product to veliparib sensitivity. Overall, while the combination was considered tolerable, it had only modest activity. No preselection was done in the study, and because BRCAness exists in 20% of patients, it is perhaps not surprising that activity was modest. The lower dose of PARP inhibitor and the lack of established benefit for TMZ may also have contributed to less than robust clinical activity for this combination. Given the emerging molecular data, it seems that future studies will be more likely to identify activity if done in preselected patient populations.

TOPARP

The Trial of PARP Inhibition in Prostate Cancer (TOPARP-A) sought to determine whether patients with prostate cancers with molecularly identified defects in DNA repair benefited from full-dose olaparib therapy.[25] In this phase II study, 50 men with CRPC underwent biopsy of metastatic disease and targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase chain reaction. The primary endpoint was response rate (either objective response or reduction of 50% in PSA level or reduction in circulating tumor cells). All had previously received docetaxel, and most had been treated with abiraterone or enzalutamide (98%) and cabazitaxel (58%). Patients were grouped according to the presence or absence of a homozygous deletion of or deleterious mutation in DNA damage response genes, which predict sensitivity to PARP inhibition. Overall, 16 of 49 evaluable patients (33%) were biomarker positive (indicative of homozygous deleterious changes in BRCA1/2, ATM, Fanconi anemia genes, or CHEK2). Of these, five patients had germline and somatic events (three patients with germline BRCA2 and three patients with germline ATM deletions or mutations). Of the 16 patients with deleterious changes in DNA repair genes, 14 (88%) responded to olaparib. The median overall survival for patients with biomarker-positive DRD tumors who received olaparib was 13.8 months, compared with 7.5 months for those with biomarker-negative tumors (P = .05). Interestingly, two biomarker-negative patients also met criteria for response to olaparib. Although one was a longer-term responder still on therapy at the time of publication, this particular patient did harbor monoallelic deletions of both BRCA2 and PALB2 that did not meet criteria for the prespecified biomarker-positive category but that may have contributed to tumor sensitivity. Toxicity was as expected, with patients displaying grade 3 or 4 anemia (10/50), fatigue (6/50), leukopenia (3/50), thrombocytopenia (2/50), and neutropenia (2/50). These results illustrate the feasibility of using molecular profiling to identify prostate cancers that display molecular features suggestive of sensitivity to PARP inhibition (BRCAness).

NCI 9012

ETS gene fusions—which result from gene rearrangement and juxtaposition of an androgen-responsive gene, such as TMPRSS2, to an ETS transcription factor gene, such as ERG or ETV1—occur in 50% to 60% of prostate cancers.[41,42] ETS transcription factors may also physically interact with PARP1, and PARP1 activity may be required for ETS-mediated invasion, transcription, and metastasis.[13] Androgen receptor–mediated transcription may also promote DNA DSBs and requires PARP activity for efficient repair.[43-45] Therefore, therapeutic targeting of androgen receptor signaling and PARP1 activity using abiraterone and veliparib is an attractive strategy in the management of metastatic prostate cancer.

A randomized phase II clinical trial in patients with metastatic CRPC was recently completed; it examined whether ETS fusion is a biomarker of response to abiraterone or abiraterone plus veliparib. In this study, 148 patients with metastatic CRPC underwent biopsy followed by assessment of ETS fusion status and then random assignment to either abiraterone alone or abiraterone plus veliparib. The primary endpoint was confirmed PSA response in patients receiving either abiraterone alone or combination therapy, stratified by ETS status. Secondary endpoints included safety, objective response rate, progression-free survival, and whether DNA repair gene deficiency (homozygous deletions of or deleterious mutations in: BRCA1, BRCA2, ATM, FANCA, PALB2, RAD51B, RAD51C) predicts response. This trial has now completed enrollment, and preliminary results will be presented at the American Society of Clinical Oncology 2016 Annual Meeting. Although final results are pending, the study does illustrate the feasibility of a large-scale metastatic tissue–based, biomarker-driven trial involving PARP inhibition in patients with metastatic CRPC. This study will also begin to ascertain the role of ETS fusions in determining response to PARP inhibitor therapy and will further explore the contribution of DRD to patient outcomes in those treated with standard therapy (abiraterone arm) and those treated with PARP inhibition (abiraterone plus veliparib arm).

Future studies

Given the data from the studies discussed previously and the enthusiasm for molecularly targeted trials in oncology, there is interest in further testing of PARP inhibition in prostate cancer patients. Multiple trials have recently been completed, are actively enrolling, or are nearing activation within this space (see Table, ClinicalTrials.gov).

Olaparib. Olaparib is the agent that is farthest along in clinical development and has an FDA indication in ovarian cancer. Olaparib also has the most active or pending studies in prostate cancer patients. TOPARP continues to enroll patients with metastatic CRPC, with a target accrual of 98 patients (ClinicalTrials.gov identifier: NCT01682772). There is a randomized double-blind, placebo-controlled phase II study of abiraterone plus olaparib or placebo for patients with metastatic CRPC who received prior docetaxel therapy (ClinicalTrials.gov identifier: NCT01972217). This trial, which is similar to the NCI 9012 study, has completed enrollment, but results are pending. Another trial is examining the biologic effect of olaparib on prostate cancer specimens when given alone or in combination with degarelix prior to prostatectomy (ClinicalTrials.gov identifier: NCT02324998). Furthermore, there is an open-label phase II study to assess the efficacy and safety of olaparib in patients with BRCA1 or BRCA2 mutations (regardless of tumor type), which is ongoing but no longer enrolling patients (ClinicalTrials.gov identifier: NCT01078662).

Veliparib. NCI 9012 (discussed previously) will help determine whether veliparib has potential therapeutic activity in metastatic CRPC and may identify molecularly determined subsets of disease (ie, ETS fusion–positive, DRD-positive) that might be expected to show the most benefit. The results of this study may help determine whether additional studies of this agent within the prostate cancer space are warranted.

Niraparib. The Hoosier Cancer Research Network has a planned phase I study of the combination of enzalutamide and niraparib for patients with metastatic CRPC (ClinicalTrials.gov identifier: NCT02500901), which has not yet begun enrollment. The primary endpoint of this study will be determination of MTD and dose-limiting toxicity.

Talazoparib. Although no prostate cancer–specific trials using other PARP inhibitors are currently active, several trials for molecularly targeted patient populations or phase I trials for toxicity assessment in combination with chemotherapy are ongoing; these provide some information on prostate cancer populations, depending on the types of solid tumors enrolled. There is a phase I trial of talazoparib in combination with carboplatin and paclitaxel (ClinicalTrials.gov identifier: NCT02317874) and another for patients with solid tumors and hepatic and renal dysfunction (ClinicalTrials.gov identifier: NCT02567396).

Precision Targeting of the PARP Pathway in Prostate Cancer

PARP inhibitors are a promising therapeutic option for men with prostate cancer. There is good evidence that men with either germline or somatic mutations in DNA repair pathways can derive therapeutic benefit from inhibition of PARP1/2, which blocks repair of SSB, driving persistent DSBs that lead to cancer cell lethality. Preclinical data also suggest that PARP inhibition may produce benefits by targeting chromatin and gene transcription, which implies that clinical benefits may extend beyond patients with DRD tumors.[12] To continue to develop PARP inhibitors within the prostate cancer field, we will need to develop and refine a set of biomarkers for use in selecting the right patient populations for these agents and then incorporate these biomarkers into prospective studies. As part of a precision therapy strategy, PARP inhibitors will likely play an important role in the management of prostate cancer in the near future.

It is now feasible to comprehensively profile the mutational, epigenetic, and gene expression changes in men with prostate cancer, and we are beginning to use this information to guide treatment choices.[7] Unfortunately, the functional relevance of many of the molecular features uncovered in these profiles is not completely understood. DNA repair processes are complex and require many genes for efficient repair of various types of DNA damage. Most past and ongoing studies focused on patients with specific molecular features, such as BRCA1, BRCA2, ATM, FANCA, PALB2, RAD51B, and RAD51C mutations. While mutations of these genes are likely to affect sensitivity to PARP inhibitors, mutations in other DNA repair or transcription factor genes may as well, and identification of those genes could expand the patient population that could benefit from therapy. Determination of whether other genes are susceptible to PARP inhibitor therapy will require robust preclinical models with a wide selection of genetic changes that reflect human disease; such models can be used to determine whether additional mutations and epigenetic or gene expression changes also result in PARP inhibitor sensitivity. Given the potential infrequency of many of the individual mutations that might sensitize to PARP inhibitors, large-scale registries that catalog mutations and their responsiveness to therapies may be needed.

As we define the molecular features that suggest sensitivity to PARP inhibition, the challenge will then become understanding the best strategy for incorporating these targeted agents into our standard treatment algorithms. In the context of prostate cancer, PARP inhibitors could be considered in high-risk patient populations in an adjuvant manner, before or with androgen deprivation therapy (ADT) in patients with newly metastatic disease, or in the setting of castration-resistant disease before or after the many other therapeutic options. To date, most trials in the prostate cancer space have been in the castration-resistant setting, perhaps because mutations in DNA damage genes may become more common as the disease progresses.[25] Nonetheless, there is no reason to assume that patients who harbor mutations may not benefit earlier in the disease course. Adjuvant use of PARP inhibitors in those with high-risk or micrometastatic disease could conceivably render patients disease free. Similarly, the combination of ADT and PARP inhibitors in early metastatic disease may provoke prolonged progression-free intervals similar to the situation with early docetaxel therapy but with less toxicity.[4,5] In the context of castration-resistant disease, it is reasonable to hypothesize that the combination of PARP inhibitors with hormonal agents such as abiraterone or enzalutamide or with chemotherapies might act synergistically to promote disease control.

The trials to examine these questions may be more challenging to design and execute because patients with sensitizing molecular changes represent a limited subset of total patients with prostate cancer. This means that in order to identify the subset that will benefit, many will need to be screened.[25] Because most molecular analyses are done using biopsy tissue, screening and cost may be challenging factors. In addition, the natural history of patients with DNA damage pathway mutations may also be distinct from those without such mutations. It is conceivable that mutations in DNA damage response genes may modulate patient response to standard hormonal agents, chemotherapy, or radium because all three of these therapeutic modalities have the potential to induce DNA damage in prostate cancer cells. Given these caveats, it will be essential to design an efficient precision medicine clinical trial pipeline that can rapidly molecularly profile patient tumors, assign to a therapeutic intervention, and then assess the complex resulting data and analyze results according to molecular categories.

PARP inhibitors have the potential to be a promising addition to the therapeutic arsenal used to treat prostate cancer and other solid tumors that harbor the appropriate molecular features. The transition from a standard, one-size-fits-all approach to a targeted, precision medicine strategy in which an individual prostate cancer patient’s tumor biology will guide choice of therapy will require careful planning and thought. The inclusion of PARP-targeted therapies before, after, with, or in place of standard hormonal therapies and chemotherapies will need to be defined so as to maximize antitumor effect and patient survival. Hopefully, application of these novel combinations in those most likely to benefit will ultimately lead to longer and better lives for patients with prostate cancer.

Financial Disclosure: Dr. Hussain is the principal investigator for a clinical trial of veliparib through the Cancer Therapy Evaluation Program (for AbbVie), and is collaborating on a clinical trial of olaparib for AstraZeneca.

David B. Solit, MD
Philip W. Kantoff, MD
Memorial Sloan Kettering Cancer Center, New York, New York

How an Ovarian Cancer Drug Came to Have ‘Breakthrough Therapy Designation’ for Prostate Cancer

With the emergence of precision medicine, clinicians can now take advantage of high-throughput tumor sequencing to identify driver mutations in individuals with cancer, with the goal of matching these with effective therapies. Since driver mutations can be shared across cancer types, precision medicine has also challenged the notion that cancer types, as defined by site of origin, are completely separate entities. One such example is the use of vemurafenib in multiple BRAF V600–mutant cancers. Another example is that of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors and prostate cancer. It is now recognized that DNA repair abnormalities, including and most notably BRCA2 mutations, are found frequently in the germline and as somatic mutations in the tumors in men with metastatic prostate cancer. Moreover, recent studies have demonstrated promising activity for olaparib—a drug approved for use in BRCA-mutated ovarian cancer—in men with castration-resistant disease and germline or somatic DNA repair abnormalities. This has led the US Food and Drug Administration to confer “breakthrough therapy designation” on olaparib, based on the strong belief that the drug will ultimately be approved for this indication.

What Questions Should Future Research on PARP Inhibitors for Prostate Cancer Focus on?

Many questions still remain unanswered. These include:

1) Given the pleiotropic effects of PARP inhibitors, which activities are the most critical and which PARP inhibitors are best for each disease/mutation scenario?

2) Have we identified the full gamut of DNA repair abnormalities that might respond to PARP inhibition?

3) Can we extend the spectrum of patients eligible for PARP inhibitors to those who are homologous recombination–proficient, by combining PARP inhibitors with therapies such as alkylating agents or antiangiogenic agents like cediranib?

4) Can we identify patients early on in their disease course in whom PARP inhibition may contribute to a curative strategy?

 

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Topoisomerase 1 & II inhibitors and cancer therapy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Topoisomerase 1 & II Inhibitors and Cancer Therapy

Julia MoukharskayaClaire Verschraegen,

Hematology/Oncology Clinics of North America  June 2012; Volume 26, Issue 3:507–525     doi:10.1016/j.hoc.2012.03.002

KEY POINTS

Topoisomerase 1 inhibitors cure human cancer xenografts in animal models, more so than most other chemotherapy agents.

However, their activity in patients with cancer is modest.

Ongoing research is studying the optimal analogs that could reproduce animal data in the cancer population.

This article analyzes the clinical research with topoisomerase 1 inhibitors in ovarian cancer.

The first type I topoisomerase (Top1) inhibitors were found in the wood bark of Camptotheca acuminata, an oriental tree, the powder or injectable extracts of which have been used in traditional Chinese medicine.1 The class was named camptothecin (CPT) for the basic CPT compound (Fig. 1). Clinical studies of this group of drugs were initiated in the 1970s, and in the 1980s the Top1 enzyme was identified as the cellular target of CPT.2,3 Topoisomerases relax the DNA supercoiling and perform catalytic functions during replication and transcription.4 There are two classes of topoisomerases. Type I enzymes cleave one strand of DNA and type II cleave both strands. Six topoisomerase genes have been identified in mammalian somatic cells within these two classes. Type IA enzymes consist of Top3 a and Top3 b; type IB consist of Top1 and Top1mt (mitochondrial); and type IIA consist of Top2 a and Top2 b. CPT is an inhibitor of Top1. Top1 cleaves the DNA phosphodiester backbone, nicking one strand of the DNA duplex and forming a Top1-DNA reversible cleavage complex by covalent bonding of a tyrosine residue. Single-strand breaks induced by Top1 help untangle excessive DNA supercoils during DNA replication and transcription (Fig. 2).5,6 Top1 is essential for survival.

 

Catalytic topoisomerase II inhibitors in cancer therapy

AK Larsen, AE Escargueil (Pierre and Marie Curie University – Paris), A Skladanowski

Pharmacology & Therapeutics  Aug 2003; 99(2):167-181      http://dx.doi.org:/10.1016/S0163-7258(03)00058-5

The nuclear enzyme DNA topoisomerase II is a major target for antineoplastic agents. All topoisomerase II-directed agents are able to interfere with at least one step of the catalytic cycle. Agents able to stabilize the covalent DNA topoisomerase II complex (also known as the cleavable complex) are traditionally called topoisomerase II poisons, while agents acting on any of the other steps in the catalytic cycle are called catalytic inhibitors. Thus, catalytic topoisomerase II inhibitors are a heterogeneous group of compounds that might interfere with the binding between DNA and topoisomerase II (aclarubicin and suramin), stabilize noncovalent DNA topoisomerase II complexes (merbarone, ICRF-187, and structurally related bisdioxopiperazine derivatives), or inhibit ATP binding (novobiocin). Some, such as fostriecin, may also have alternative biological targets. Whereas topoisomerase II poisons are used solely for their antitumor activities, catalytic inhibitors are utilized for a variety of reasons, including their activity as antineoplastic agents (aclarubicin and MST-16), cardioprotectors (ICRF-187), or modulators in order to increase the efficacy of other agents (suramin and novobiocin). In this review, the mechanism and biological activity of different catalytic inhibitors is described, with emphasis on therapeutically used compounds. We will then discuss future development and applications of this interesting class of compounds.

Fig. 1. The catalytic cycle of DNA topoisomerase II. The ATPase domains of topoisomerase II are shown in light blue, the core domain in dark blue, and the active site tyrosine residue in red. The C-terminal domain of the enzyme is not included in the diagram since its orientation, with respect to the rest of the molecule, is not known. The catalytic cycle is initiated by enzyme binding to two double-stranded DNA segments called the G segment (in red) and the T segment (in green) (Step 1). Next, two ATP molecules are bound, which is associated with dimerization of the ATPase domains (Step 2). The G segment is cleaved (Step 3) and the T segment is transported through the break in the G segment, which is accompanied by the hydrolysis of one ATP molecule (Step 4). The G segment is then religated and the remaining ATP molecule is hydrolyzed (Step 5). Upon dissociation of the two ADP molecules, the T segment is transported through the opening in the C-terminal part of the enzyme (Step 6) followed by closing of this gate. Finally, the N-terminal ATPase domains reopen, allowing the enzyme to dissociate from DNA (Step 7). Data from Berger et al. (1996), Baird et al. (1999), Brino et al. (2000), and Hu et al. (2002).     https://www.researchgate.net/profile/Alexandre_Escargueil3/publication/10638629/figure/fig1/AS:281505667534857@1444127589543/Fig-1-The-catalytic-cycle-of-DNA-topoisomerase-II-The-ATPase-domains-of-topoisomerase.png

 

Targeting HIF-1 for cancer therapy

Gregg L. Semenza

Nature Reviews Cancer 3, 721-732 (October 2003) |      http://dx.doi.org:/10.1038/nrc1187   http://www.nature.com/nrc/journal/v3/n10/full/nrc1187.html

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1α overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

 

Targeting DNA topoisomerase II in cancer chemotherapy

Recent molecular studies have greatly expanded the biological contexts where Top2 plays critical roles, including DNA replication, transcription and chromosome segregation. Although the biological functions of Top2 are important for insuring genomic integrity, the ability to interfere with Top2 and generate enzyme mediated DNA damage is an effective strategy for cancer chemotherapy. The molecular tools that have allowed understanding the biological functions of Top2 are also being applied to understanding the details of drug action. These studies promise a more refined ability to target Top2 as an effective anti-cancer strategy.

An important reason why Top2 has held the interest of researchers studying cancer was the discovery that active anti-cancer drugs, notably etoposide and doxorubicin target Top21. These studies showed that most clinically active drugs that target Top2 generate enzyme mediated DNA damage24. Since etoposide and doxorubicin are highly active anti-cancer agents in many different settings, an identification of a critical target of these drugs was a major landmark in the pharmacology of anti-cancer drugs.

Recent work has shown that there may be contexts where the level of Top2 protein predicts clinical activity (as well as many contexts where it does not). With the understanding of mechanisms of drug action and improved patient survival rates has come the appreciation that clinical treatment with drugs targeting Top2 can lead to the dire consequence of secondary malignancies. An important goal of present and future work is to maximize therapeutic efficacy of therapy using Top2 targeting agents while minimizing the risks of secondary malignancy and other toxicities. This review highlights recent work that is relevant to maximizing the potential of Top2 as an anti-cancer drug target.

Inhibition of Top2 activity by anti-cancer agents

Drugs targeting Top2 are divided into two broad classes. The first class, which includes most of the clinically active agents including etoposide, doxorubicin, and mitoxantrone, lead to increases in the levels of Top2:DNA covalent complexes. Because these agents generate a “lesion” that includes DNA strand breaks and protein covalently bound to DNA, these agents have been termed Top2 poisons. A second class of compounds inhibits Top2 catalytic activity, but do not generate increases in the levels of Top2 covalent complexes. This second class of agents is thought to kill cells through elimination of the essential enzymatic activity of Top2 and is therefore termed catalytic inhibitors (Fig. 1).

Figure 1   Mechanisms of inhibiting of Top2
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Mechanisms of inhibiting of Top2

Top2 can be inhibited at several different points in the enzyme reaction cycle, which can generate different biochemical and cellular consequences. One simple mode of inhibition is to inhibit a step early in the enzyme reaction cycle. For example, competitive inhibitors of ATP binding prevent strand passage, and do not generate enzyme mediated DNA damage. While agents such as novobiocin and coumermycin (not shown on the figure) inhibit both prokaryotic and eukaryotic Top2s, they are either less potent as well as relatively nonspecific (e.g., novobiocin) or are poorly taken up by mammalian cells (e.g., coumermycin). Similar effects would occur with inhibitors that prevent the binding of Top2 to DNA such as aclarubicin. Agents that prevent DNA cleavage by Top2, such as merbarone would also be expected to act as simple catalytic inhibitors. While merbarone clearly prevents DNA cleavage by Top2126, merbarone clearly affects other targets besides Top2. A second mode of inhibition is blocking the catalytic cycle after DNA is cleaved but prior to DNA religation. This mode of inhibition occurs for most currently used Top2 targeting agents including anthracyclines and epipodophyllotoxins, as well as for agents that target prokaryotic type II topoisomerases. These agents prevent enzyme turnover, and therefore greatly inhibit the enzyme catalytic activity, however, the clearest effect is the generation of high levels of Top2:DNA covalent complexes. Therefore, these inhibitors generate DNA damage, and interfere with many DNA metabolic events such as transcription and replication. Since agents of this class convert Top2 into an agent that induces cellular damage, they have been termed topoisomerase poisons. Top2 can be inhibited after strand passage is completed, but prior to ATP hydrolysis and dissociation of N-terminal dimerization. Bisdioxopiperazines such as dexrazoxane (ICRF-187) inhibit both ATP hydrolysis and maintain Top2 as a closed clamp 74. As is the case with Top2 poisons, bisdioxopiperazines inhibit Top2 catalytic activity mainly by blocking enzyme turnover. Although these agents are frequently termed catalytic inhibitors, they leave Top2 trapped on DNA, and may interfere with DNA metabolism in ways distinct from the inhibitors described in pathway (A). Nonetheless, since bisdioxopiperazines are relatively specific for Top2, they are the most commonly used catalytic inhibitors of Top2 in mammalian cells 143.

There are several lines of evidence indicating the importance of the distinction between Top2 poisons and Top2 catalytic inhibitors. Studies in yeast and mammalian cells demonstrated that resistance to Top2 poisons is recessive, i.e., presence of a drug resistant Top2 in the presence of a drug sensitive allele results in cells that are drug sensitive (reviewed in 5,6). The importance of enzyme mediated DNA damage is also demonstrated by observations that Top2 poisons rapidly elicit DNA damage responses such as ATM phosphorylation and activation of downstream damage responses79. Resistance to Top2 targeting drugs in mammalian cells is frequently associated with reduced expression of Top2 isoforms6, suggesting that resistance is mediated through a reduction in enzyme mediated DNA damage, rather than through enhancing available enzyme activity (where resistance would arise from increased expression of Top2 isoforms).

The generation of high levels of Top2 DNA covalent complexes has profound effects on cell physiology. Top2 poisons effectively block transcription and replication. DNA strand breaks are rapidly detected following treatment with Top2 poisons, and most of the strand breaks are protein linked, as expected10,11. Cells subsequently commit to apoptosis, in fact etoposide is a very commonly used agent to study apoptotic processes12.

The pattern of responses observed with catalytic inhibitors of Top2 differ from that observed with Top2 poisons, albeit with several important complications. Most catalytic inhibitors of Top2 are not specific for Top2 inhibition (see Box 1) with the exception of bisdioxopiperazines. While bisdioxopiperazines generate DNA damage responses following long exposure13, they do not produce a DNA damage response following short term exposure1417. Importantly, in cell culture experiments, catalytic inhibitors of Top2 antagonize the toxicity of Top2 poisons18, indicating that the agents act by separable mechanisms. An important and still unanswered question is whether Top2 inhibitors that are not poisons might be active anti-cancer agents. This issue is addressed in the concluding sections of this review.

Box 1. Many different classes of compounds target Topoisomerase II

Drugs targeting topoisomerase II fall into two categories, Top2 poisons and Top2 catalytic inhibitors. Many Top2 poisons have demonstrated anti-cancer activity. Top2 poisons can be further sub-divided into intercalating and non-intercalating poisons. The intercalators are chemically diverse, and include doxorubicin and other anthracyclines, mitoxantrone, mAMSA, and a variety of other compounds that are not currently in clinical use such as amonafide and ellipticine5. Other than their ability to intercalate in DNA, there is no obvious chemical similarity that could explain the ability of these compounds to trap Top2. Importantly, some compounds, such as oAMSA and ethidium bromide have little ability to poison Top2, suggesting that intercalation of a small molecule is insufficient to trap Top2 as a covalent complex on DNA1,110. Some of the intercalating Top2 targeting drugs, notably the anthracyclines, produce a variety of effects on cells, including many effects that are independent of their action against Top2. For example, doxorubicin is known to produce free radicals, to cause membrane damage, and to induce protein:DNA crosslinks. Whether Top2 is the most important target of anthracyclines remains a controversial issue, (reviewed in 111), although some of the results presented in the text support the hypothesis that Top2 is the most relevant target for both clinical response and cardiotoxicity. For alternate hypotheses, see 112114.

Several classes of compounds have been described that inhibit Top2 activity but do not increase DNA cleavage. Most prominent are the bisdioxopiperazines, which inhibit the enzyme ATPase activity non-competitively and trap Top2 as a closed clamp74,117,118. ICRF-187, a bisdioxopiperazine, is used as a cardioprotectant in some patients treated with anthracyclines. Other Top2 catalytic inhibitors include novobiocin119121, merbarone122, and the anthracycline aclarubicin123. All three compounds have significant targets besides Top2121,124,125; therefore these compounds have not been useful in assessing the feasibility of using catalytic inhibitors of Top2 as an anti-cancer therapy. Merbarone has attracted interest because it is the only agent that has been found to inhibit Top2 cleavage of DNA but not affect protein:DNA binding126. QAP1 is a newly described purine analog that was rationally designed to target the Top2 ATPase activity127. This compound may be particularly useful in assessing the effects of catalytic inhibition of Top2. Several other catalytic inhibitors have been described, however, their detailed mechanism of action has not been explored.

The future of Top2 as a drug target

Is there a need for new and different Top2 drugs? The first answer to this question is a resounding yes, since Top2 targeting is clearly successful in a wide variety of contexts. It is clear from broiad clinical experience that Top2 targeting drugs can be safely and effectively combined with many other agents. The Top2 targeting drugs in clinical use were identified not based on their activity against Top2, but mainly on empirical anti-tumor activity. Therefore, it would be expected that rational screening would lead to potent and specific Top2 poisons. It would be very desirable to know if greater potency and specificity would enhance clinical response.

At the time etoposide and doxorubicin were approved for use, we did not know of the existence of Top2β. The results reviewed in this article suggest that the targeting of Top2β leads to several undesirable consequences and little clear benefit. The negative effects of targeting Top2β include the induction of cardiotoxicity, and potentially a major role in secondary malignancies. On the other hand, there are potential benefits of targeting Top2β, especially the ability to kill non-proliferating cells. While targeting Top2β may contribute to toxicity, it may also be important for eliminating cancer cells that function as cancer stem cells.

An important question is whether isotype specific Top2 poisons can be identified, since the two enzymes share catalytic mechanisms, and a great deal of amino acid homology in their catalytic domains. It has been previously suggested that the intercalators mAMSA and mitoxantrone confer cytotoxicity mainly due to targeting Top2β106. More recently, a novel intercalator NK314 has been reported to be highly specific for Top2α107,108. Toyoda and colleagues also suggested that etoposide and doxorubicin generate greater cytotoxicity by targeting Top2α. Taken together, these results suggest that agents specific for Top2α may possible, and may be useful for having both greater anti-tumor activity, and reduced toxicitiy.

The search for improved Top2 targeting drugs will require further advances in both the biochemistry and structural biology of drug action. While the structures that have already been determined have provided important insights into the biochemistry of Top2, the only structure of Top2 bound to a drug that has been determined is the ATPase domain of Top2 bound to ICRF-187109. The grail for understanding the biochemistry of a drug like etoposide is the determination of a ternary complex between drug, protein, and DNA. Hopefully, the structures of the breakage/reunion domains of Top2α and Top2β, especially their DNA bound forms, will be solved soon.

An interesting question related to drug development is whether catalytic inhibitors of Top2 might be active anti-cancer agents. Much of the literature on the action of Top2 poisons implicitly assumes that they inhibit Top2 activity. Compared to many other enzyme inhibitors, any of the currently described Top2 targeting agents has relatively poor potency (for example, the Ki of etoposide for Top2 is in the 5-20 μM range, the Ki for ICRF-193 is in the 1-2 μM range). The availability of crystal structures provides the tools for addressing whether Top2 inhibition will be a valuable strategy (and will provide tools needed to answer many important biological questions).

The recent biological insights in transcription, replication and checkpoint control also offer ways to better understand drug action and resistance. Since cancer cells can clearly present with altered topoisomerase levels, whether by amplification or changes in gene regulation, these alterations provide an opportunity for enhanced therapeutic index. Finally, active anti-cancer therapy requires an understanding of how cancer cells ‘make a living’, and topoisomerases clearly are central to many of these core biological functions.

At a glance

  • Top2 is the target of several important classes of anti-cancer drugs, including the epipodophyllotoxin etoposide, and the anthracycline doxorubicin.
  • Most clinically active drugs that target Top2 kill cells by trapping an enzyme intermediate termed the covalent complex. Therefore, the principal action of Top2 targeting drugs currently used are to generate enzyme mediated DNA damage.
  • A recent structure of the breakage reunion domain of Top2 bound to DNA has been determined. This structure is likely to be of great use in understanding the protein determinants of the action of drugs targeting Top2. A drug:protein:DNA ternary complex would be extremely valuable, but has not yet been determined.
  • Top2 mediated DNA damage is repaired by multiple pathways. The DNA damage includes DNA strand breaks and proteins covalently bound to DNA. Repair of Top2 damage requires double strand break repair pathways, and other pathways specific for the removal of protein:DNA adducts.
  • Sensitivity to Top2 targeting drugs depends in part on levels of Top2 protein. Cells overexpressing Top2 are hypersensitive to Top2 poisons while cells expressing low levels of Top2 are relatively drug resistant. Top2α is frequently co-amplified with ERBB2. This can lead to some tumors with elevated levels of Top2α.
  • An important side effect of targeting Top2 with Top2 poisons are secondary malignancies arising from drug induced translocations. Top2β may be the Top2 isoform that is most responsible for secondary malignancies caused by Top2 targeting drugs.
  • Anthracycline use is limited by cardiotoxicity. Although the mechanism of the cardiotoxicity is poorly understood, recent results suggest that anthracyclines acting against Top2β may contribute significantly to cardiotoxicity. There may be considerable benefit to developing Top2 targeting drugs specific for the Top2α isoform.
  • Catalytic inhibition of Top2 may also be a useful anti-cancer strategy. New compounds are being developed to test this possibility.

 

Anticancer Chemotherapy – Topoisomerase Inhibitors Part 1 …

Early effects of topoisomerase I inhibition on RNA polymerase II along transcribed genes in human cells.

Khobta A, Ferri F, Lotito L, Montecucco A, Rossi R, Capranico G.

J Mol Biol. 2006 Mar 17;357(1):127-38. Epub 2006 Jan 6.

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RNA Polymerase II Regulates Topoisomerase 1 Activity to Favor Efficient Transcription.

Baranello L, Wojtowicz D, Cui K, Devaiah BN, Chung HJ, Chan-Salis KY, Guha R, Wilson K, Zhang X, Zhang H, Piotrowski J, Thomas CJ, Singer DS, Pugh BF, Pommier Y, Przytycka TM, Kouzine F, Lewis BA, Zhao K, Levens D.

Cell. 2016 Apr 7;165(2):357-71. doi: 10.1016/j.cell.2016.02.036.

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. Topoisomerase I deficiency causes RNA polymerase II accumulation and increases AID abundance in immunoglobulin variable genes.

Maul RW, Saribasak H, Cao Z, Gearhart PJ.

DNA Repair (Amst). 2015 Jun;30:46-52. doi: 10.1016/j.dnarep.2015.03.004. Epub 2015 Mar 18.

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DNA topoisomerase I inhibition by camptothecin induces escape of RNA polymerase II from promoter-proximal pause site, antisense transcription and histone acetylation at the human HIF-1alpha gene locus.

Baranello L, Bertozzi D, Fogli MV, Pommier Y, Capranico G.

Nucleic Acids Res. 2010 Jan;38(1):159-71. doi: 10.1093/nar/gkp817. Epub 2009 Oct 23.

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TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1.

Zeng Z, Sharma A, Ju L, Murai J, Umans L, Vermeire L, Pommier Y, Takeda S, Huylebroeck D, Caldecott KW, El-Khamisy SF.

Nucleic Acids Res. 2012 Sep 1;40(17):8371-80. Epub 2012 Jun 26.

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Disifin (sodium tosylchloramide) and Toll-like receptors (TLRs): evolving importance in health and diseases.

Ofodile ON.

J Ind Microbiol Biotechnol. 2007 Dec;34(12):751-62. Epub 2007 Sep 5. Review.

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Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel.

Maede Y, Shimizu H, Fukushima T, Kogame T, Nakamura T, Miki T, Takeda S, Pommier Y, Murai J.

Mol Cancer Ther. 2014 Jan;13(1):214-20. doi: 10.1158/1535-7163.MCT-13-0551. Epub 2013 Oct 15.

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Genome-wide analysis of novel splice variants induced by topoisomerase I poisoning shows preferential occurrence in genes encoding splicing factors.

Solier S, Barb J, Zeeberg BR, Varma S, Ryan MC, Kohn KW, Weinstein JN, Munson PJ, Pommier Y.

Cancer Res. 2010 Oct 15;70(20):8055-65. doi: 10.1158/0008-5472.CAN-10-2491. Epub 2010 Sep 3.

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Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity.

Goulet ML, Olagnier D, Xu Z, Paz S, Belgnaoui SM, Lafferty EI, Janelle V, Arguello M, Paquet M, Ghneim K, Richards S, Smith A, Wilkinson P, Cameron M, Kalinke U, Qureshi S, Lamarre A, Haddad EK, Sekaly RP, Peri S, Balachandran S, Lin R, Hiscott J.

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Patterns of oligonucleotide sequences in viral and host cell RNA identify mediators of the host innate immune system.

Greenbaum BD, Rabadan R, Levine AJ.

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Gemcitabine (2′,2′-difluoro-2′-deoxycytidine), an antimetabolite that poisons topoisomerase I.

Pourquier P, Gioffre C, Kohlhagen G, Urasaki Y, Goldwasser F, Hertel LW, Yu S, Pon RT, Gmeiner WH, Pommier Y.

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. Chromatin remodeller SMARCA4 recruits topoisomerase 1 and suppresses transcription-associated genomic instability.

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A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial

Curator: Stephen J. Williams, Ph.D.

 

This post is a follow-up on the two reports found in this Open Access Journal

https://pharmaceuticalintelligence.com/2015/09/16/ovarian-cancer-survival-increased-5-months-overall-with-beta-blockers-study-the-speaker/

AND

https://pharmaceuticalintelligence.com/2013/04/08/beta-blockers-help-in-better-survival-in-ovarian-cancer/

in order to explain some of the background which went into the development of these reports.

A recent paper by Anil Sood’s group at MD Anderson in Journal of Cancer: Clinical impact of selective and nonselective beta-blockers on survival in patients with ovarian cancer describes a retrospective pathologic evaluation of ovaries from patients taking various beta blockers for currently approved indications.

The history of this finding is quite interesting and, as I remember in a talk given by Dr. Sood in mid-2000’s, a microarray conducted by his lab had showed overexpression of the β2-AR (β2 adrenergic receptor in ovarian cancer cells relative to normal epithelium. At the time it appeared an interesting result however most of the cancer (and ovarian cancer) field were concentrating on the tyrosine kinase signaling pathways as potential therapeutic targets, as much promising translational research in this area was in focus at the time. As a result of this finding and noticing that sustained β-adrenergic stimulation can promote ovarian cancer cell growth (Sood, 2006), Dr. Sood’s group have been studying the effects of β-adrenergic signaling om ovarian cancer. In addition it has been shown that propanalol can block VEGF signaling and norepinephrine increased MMP2 and MMP9 expression, an effect mediated by the β2-AR.

The above re-post of a Scoop-IT describes promising results of a clinical trial for use of selective beta blockers in ovarian cancer.   As to date, there have been many clinical trials initiated in ovarian cancer and most have not met with success for example the following posts:

Good and Bad News Reported for Ovarian Cancer Therapy

a follow-up curation on the problems encountered with the PARP-inhibitor olaparib

enough is enough: Treat ‘Each Patient as an Individual’

which contains an interview with Dr. Maurie Markman (Vice President, Patient Oncology Services, and National Director for Medical Oncology, Cancer Treatment Centers of America) and Dr. Kathy D. Miller, Indiana University School of Medicine) and discusses how each patient’s ovarian cancer is genetically unique and needs to be treated as such

Therefore the mainstay therapy is still carboplatin plus a taxane (Taxotere, Abraxane). The results of this clinical trial show a 5 month improvement in survival, which for a deadly disease like ovarian cancer is a significant improvement.

First below is a SUMMARY of the paper’s methodology and findings.

Methods:

  • Four participating institutions collected retrospective patient data and pathology reports from 1425 patients diagnosed with epithelial ovarian cancer (EOC)
  • Medical records were evaluated for use of both selective and nonselective β-blockers
  • β-blockers were used for various indications however most common indication was treatment for hypertension (71% had used β1 selective blockers while rest of patients taking β blockers were given nonselective blockers for a host of other indications)
  • most patients had stage III/IV disease and in general older (median age 63 years)
  • The authors looked at overall survival (OS) however progression free survival PFS) was not calculated

Results:

  • Hypertension was associated with decreased survival (40.1 monts versus 47.4 months for normotensive patients)
  • Overall Survival for patients on any β blockers was 47.8 months versus 42.0 months for nonusers
  • Patients receiving nonselective β blockers has an OS of 94.9 months versus 38 months for EOC patients receiving β1-selective blockers
  • No effect of diabetes mellitus on survival

Authors Note on Limitations of Study:

  • Retrospective in nature
  • Lack of documentation of dosage, trade-name and duration of β-blocker use
  • Important to stratify patients on selectivity of β-blocker since Eskander et. al. found no difference of Progression Free Survival and non-selective β-blocker
  • Several β adrenergic receptor polymorphisms may exist and no downstream biomarker evaluated to determine effect on signaling; could it be a noncanonical effect?

The goal of this brief, added curation is to paint a historical picture, and highlight the scientific findings which led up to the rationale behind this clinical trial.

How the βeta Adrenergic Receptor (βAR) Became a Target for Ovarian Cancer

.

A. βAR and its signaling over-expressed in ovarian cancer

Role of mitogen-activated protein kinase/extracellular signal-regulated kinase cascade in gonadotropin-releasing hormone-induced growth inhibition of a human ovarian cancer cell line.

Kimura A, Ohmichi M, Kurachi H, Ikegami H, Hayakawa J, Tasaka K, Kanda Y, Nishio Y, Jikihara H, Matsuura N, Murata Y.

Cancer Res. 1999 Oct 15;59(20):5133-42.

Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon stimulation of the beta 2-adrenergic receptor.

Rangarajan S, Enserink JM, Kuiperij HB, de Rooij J, Price LS, Schwede F, Bos JL.

J Cell Biol. 2003 Feb 17;160(4):487-93. Epub 2003 Feb 10.

B. Mechanistic Link Between Chronic Stress From Excess Adrenergic Stimulation and Angiogenesis and Metastasis

Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines.

Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J, Jabbari S, Rainwater K, Ritchie JM, Yang M, Sood AK.

Clin Cancer Res. 2003 Oct 1;9(12):4514-21.PMID:

Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells.

Yang EV, Sood AK, Chen M, Li Y, Eubank TD, Marsh CB, Jewell S, Flavahan NA, Morrison C, Yeh PE, Lemeshow S, Glaser R.

Cancer Res. 2006 Nov 1;66(21):10357-64.

VEGF is differentially regulated in multiple myeloma-derived cell lines by norepinephrine.

Yang EV, Donovan EL, Benson DM, Glaser R.

Brain Behav Immun. 2008 Mar;22(3):318-23. Epub 2007 Nov 5.

Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.

Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK.

Nat Med. 2006 Aug;12(8):939-44. Epub 2006 Jul 23.

Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells.

Yang EV, Sood AK, Chen M, Li Y, Eubank TD, Marsh CB, Jewell S, Flavahan NA, Morrison C, Yeh PE, Lemeshow S, Glaser R.

Cancer Res. 2006 Nov 1;66(21):10357-64.

C. In Vivo Studies Confirm In Vitro Findings That Chronic Stress Via Adrenergic overstimulation Increases Ovarian Cancer Growth

Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.

Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK.

Nat Med. 2006 Aug;12(8):939-44. Epub 2006 Jul 23.

Stress hormone-mediated invasion of ovarian cancer cells.

Sood AK, Bhatty R, Kamat AA, Landen CN, Han L, Thaker PH, Li Y, Gershenson DM, Lutgendorf S, Cole SW.

Clin Cancer Res. 2006 Jan 15;12(2):369-75.

The neuroendocrine impact of chronic stress on cancer.

Thaker PH, Lutgendorf SK, Sood AK.

Cell Cycle. 2007 Feb 15;6(4):430-3. Epub 2007 Feb 9. Review.

Surgical stress promotes tumor growth in ovarian carcinoma.

Lee JW, Shahzad MM, Lin YG, Armaiz-Pena G, Mangala LS, Han HD, Kim HS, Nam EJ, Jennings NB, Halder J, Nick AM, Stone RL, Lu C, Lutgendorf SK, Cole SW, Lokshin AE, Sood AK.

Clin Cancer Res. 2009 Apr 15;15(8):2695-702. doi: 10.1158/1078-0432.CCR-08-2966. Epub 2009 Apr 7.

Sood group wanted to mimic the surgical stress after laparoscopic surgery to see if surgical stress would promote the growth of micrometasteses remaining after surgical tumor removal. Propranolol completely blocked the effects of surgical stress on tumor growth, indicating a critical role for beta-adrenergic receptor signaling in mediating the effects of surgical stress on tumor growth. In the HeyA8 and SKOV3ip1 models, surgery significantly increased microvessel density (CD31) and vascular endothelial growth factor expression, which were blocked by propranolol treatment. Tumor growth after surgery was decreased in a mouse null for βAR. Levels of cytokines G-CSF, IL-1a, IL-6, and IL-15were increased after surgery

Stress effects on FosB- and interleukin-8 (IL8)-driven ovarian cancer growth and metastasis J Biol Chem. 2010 Nov 12;285(46):35462-70. doi: 10.1074/jbc.M110.109579. Epub 2010 Sep 8.

Shahzad MM1, Arevalo JM, Armaiz-Pena GN, Lu C, Stone RL, Moreno-Smith M, Nishimura M, Lee JW, Jennings NB, Bottsford-Miller J, Vivas-Mejia P, Lutgendorf SK, Lopez-Berestein G, Bar-Eli M, Cole SW, Sood AK.

Free PMC Article

Abstract

A growing number of studies indicate that chronic stress can accelerate tumor growth due to sustained sympathetic nervous system activation. Our recent findings suggest that chronic stress is associated with increased IL8 levels. Here, we examined the molecular and biological significance of IL8 in stress-induced tumor growth. Norepinephrine (NE) treatment of ovarian cancer cells resulted in a 250-300% increase in IL8 protein and 240-320% increase in its mRNA levels. Epinephrine treatment resulted in similar increases. Moreover, NE treatment resulted in a 3.5-4-fold increase in IL8 promoter activity. These effects were blocked by propranolol. Promoter deletion analyses suggested that AP1 transcription factors might mediate catecholamine-stimulated up-regulation of IL8. siRNA inhibition studies identified FosB as the pivotal component responsible for IL8 regulation by NE. In vivo chronic stress resulted in increased tumor growth (by 221 and 235%; p < 0.01) in orthotopic xenograft models involving SKOV3ip1 and HeyA8 ovarian carcinoma cells. This enhanced tumor growth was completely blocked by IL8 or FosB gene silencing using 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoliposomes. IL8 and FosB silencing reduced microvessel density (based on CD31 staining) by 2.5- and 3.5-fold, respectively (p < 0.001). Our findings indicate that neurobehavioral stress leads to FosB-driven increases in IL8, which is associated with increased tumor growth and metastases. These findings may have implications for ovarian cancer management.

Dopamine blocks stress-mediated ovarian carcinoma growth.

Moreno-Smith M, Lu C, Shahzad MM, Pena GN, Allen JK, Stone RL, Mangala LS, Han HD, Kim HS, Farley D, Berestein GL, Cole SW, Lutgendorf SK, Sood AK.

Clin Cancer Res. 2011 Jun 1;17(11):3649-59. doi: 10.1158/1078-0432.CCR-10-2441. Epub 2011 Apr 29.

D. Additional mechanisms iincluding JAK/STAT modulation, prostaglandin synthesis, AKT, and Slug implicated in Stress (norepinephrine) induced increase in Ovarian Tumor Growth

Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis.

Nagaraja AS, Dorniak PL, Sadaoui NC, Kang Y, Lin T, Armaiz-Pena G, Wu SY, Rupaimoole R, Allen JK, Gharpure KM, Pradeep S, Zand B, Previs RA, Hansen JM, Ivan C, Rodriguez-Aguayo C, Yang P, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK.

Oncogene. 2015 Aug 10. doi: 10.1038/onc.2015.302. [Epub ahead of print]

The antihypertension drug doxazosin suppresses JAK/STATs phosphorylation and enhances the effects of IFN-α/γ-induced apoptosis.

Park MS, Kim BR, Kang S, Kim DY, Rho SB.

Genes Cancer. 2014 Nov;5(11-12):470-9.

hTERT mediates norepinephrine-induced Slug expression and ovarian cancer aggressiveness.

Choi MJ, Cho KH, Lee S, Bae YJ, Jeong KJ, Rha SY, Choi EJ, Park JH, Kim JM, Lee JS, Mills GB, Lee HY.

Oncogene. 2015 Jun;34(26):3402-12. doi: 10.1038/onc.2014.270. Epub 2014 Aug 25.

The antihypertension drug doxazosin inhibits tumor growth and angiogenesis by decreasing VEGFR-2/Akt/mTOR signaling and VEGF and HIF-1α expression.

Park MS, Kim BR, Dong SM, Lee SH, Kim DY, Rho SB.

Oncotarget. 2014 Jul 15;5(13):4935-44.

Meeting Abstracts on the Subject

From 2007 AACR Meeting

Neuroendocrine Modulation of Signal Transducer and Activator of Transcription-3 in Ovarian Cancer

  1. Requests for reprints:
    Anil K. Sood, Departments of Gynecologic Oncology and Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 1155 Herman Pressler, CPB6.3244, Unit 1362, Houston, TX 77230-1439. Phone: 713-745-5266; Fax: 713-792-7586; E-mail: asood@mdanderson.org.

Abstract

There is growing evidence that chronic stress and other behavioral conditions are associated with cancer pathogenesis and progression, but the mechanisms involved in this association are poorly understood. We examined the effects of two mediators of stress, norepinephrine and epinephrine, on the activation of signal transducer and activator of transcription-3 (STAT3), a transcription factor that contributes to many promalignant pathways. Exposure of ovarian cancer cell lines to increasing concentrations of norepinephrine or epinephrine showed that both independently increased levels of phosphorylated STAT3 in a dose-dependent fashion. Immunolocalization and ELISA of nuclear extracts confirmed increased nuclear STAT3 in response to norepinephrine. Activation of STAT3 was inhibited by blockade of the β1- and β2-adrenergic receptors with propranolol, and by blocking protein kinase A with KT5720, but not with the α receptor blockers prazosin (α1) and/or yohimbine (α2). Catecholamine-mediated STAT3 activation was not inhibited by pretreatment with an anti–interleukin 6 (IL-6) antibody or with small interfering RNA (siRNA)–mediated decrease in IL-6 or gp130. Regarding the effects of STAT3 activation, exposure to norepinephrine resulted in an increase in invasion and matrix metalloproteinase (MMP-2 and MMP-9) production. These effects were completely blocked by STAT3-targeting siRNA. In mice, treatment with liposome-incorporated siRNA directed against STAT3 significantly reduced isoproterenol-stimulated tumor growth. These studies show IL-6–independent activation of STAT3 by norepinephrine and epinephrine, proceeding through the β1/β2-adrenergic receptors and protein kinase A, resulting in increased matrix metalloproteinase production, invasion, and in vivo tumor growth, which can be ameliorated by the down-regulation of STAT3. [Cancer Res 2007;67(21):10389–96]

From 2009 AACR Meeting

Abstract #2506: Functional \#946;2 adrenergic receptors (ADRB2) on human ovarian tumors portend worse clinical outcome

Abstract

Objective: Stress hormones such as catecholamines can augment tumor metastasis and angiogenesis; however, the prevalence and clinical significance of adrenergic receptors in human ovarian cancer is unknown and is the focus of the current study. Methods: After IRB approval, paraffin-embedded samples from 137 patients with invasive epithelial ovarian carcinoma were examined for \#946;1- and \#946;2-adrenergic receptor (ADRB1 and ADRB2, respectively) expression. Correlations with clinical outcomes were determined using parametric and non-parametric tests. Survival analyses were performed using the Kaplan-Meier method. Expression of ADRB1 and -2 was examined by quantitative RT-PCR in 15 freshly extracted human ovarian carcinoma cells. Human ovarian carcinoma cells then underwent time-variable adrenergic stimulation, and tumorigenic and angiogenic cytokine levels were examined by ELISA. Results: Sixty-six percent of the tumors had high expression of ADRB1; 80% of specimens highly expressed ADRB2. Univariate analyses demonstrated that high ADRB1 expression was associated with serous histology (p=0.03) and the presence of ascites (p=0.03), while high expression of ADRB2 was associated with advanced stage (p=0.008). Moreover, high ADRB2 expression was associated with the lower overall survival (2.2 vs. 6.5 years; p<0.001). In multivariate analysis, controlling for FIGO stage, grade, cytoreduction, age, and ADRB expression, only FIGO stage, cytoreduction status, age, and ADRB status retained statistical significance in predicting overall survival. In tumor cells freshly isolated from human ovarian cancers, 75% of samples had high expression of ADRB2 while most lacked ADRB1 compared to normal surface epithelium. Stimulation of the freshly isolated ADRB2-positive human ovarian cancer cells with norepinephrine resulted in increased levels of cAMP and increased angiogenic cytokines IL-6 and VEGF. Conclusions: ADRB2 are frequently found on human ovarian tumors and are strongly associated with poor clinical outcome. These findings support a direct mechanism by which stress hormones modulate ovarian cancer growth and metastasis as well as provide a basis for therapeutic targeting.

And from the 2015 AACR Meeting:

Abstract 3368: Sustained adrenergic signaling activates pro-inflammatory prostaglandin network in ovarian carcinoma

  1. Archana S. Nagaraja1,

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA

Abstract

Purpose: Catecholamine mediated stress effects are known to induce production of various pro-inflammatory cytokines. However, the mechanism and functional effect of adrenergic signaling in driving inflammation via pro-inflammatory metabolites is currently unknown. Here we address the functional and biological consequences of adrenergic-induced Cox2/PGE2 axis activation in ovarian cancer metastasis.

Methods: We first analyzed global metabolic changes in tumors isolated from patients with known Center for Epidemiologic Studies Depression Scale (CES-D; depressive) scores and tumoral norepinephrine (NE) levels. Beta-adrenergic receptor (ADRB) positive cells (Skov3 and HeyA8) were used to study gene and protein levels of PTGS2 (cyclooxygenase2), PTGES (prostaglandin E synthase) and metabolite PGE2 in vitro and in vivo. To study tumor-specific effects on catecholamine-derived expression of PTGS2, we used a novel DOPC delivery system of PTGS2 siRNA.

Results: Our results revealed that levels of PGs were significantly increased in patients with high depressive scores (>16). PGE2 was upregulated by 2.38 fold when compared to the low CES-D scores. A similar trend was also observed with other pro-inflammatory eicosanoids, such as 6-keto prostaglandin F1 Alpha (2.03), prostaglandin A2 (1.39) and prostaglandin E1 (1.39). Exposure to NE resulted in increased PTGS2 and PTGES (prostaglandin E2 synthase) gene expression and protein levels in Skov3 and HeyA8. PGE2 ELISA confirmed that upon treatment with NE, PGE2 levels were increased in conditioned medium from Skov3 and HeyA8 cells. Treatment with a broad ADRB agonist (isoproterenol) or ADRB2 specific agonist (terbutaline) led to increases in expression of PTGS2 and PTGES as well as PGE2 levels in supernatant. Conversely, treatment with a broad antagonist (propranolol) or an ADRB2 specific antagonist (butoxamine) in the presence of NE abrogated gene expression changes of PTGS2 and PTGES. ChIP analysis showed enrichment of Nf-kB binding to the promoter region of PTGS2 and PTGES by 2.4 and 4.0 fold respectively when Skov3ip1 cells were treated with NE. Silencing PTGS2 resulted in significantly decreased migration (40%) and invasion (25%) of Skov3 cells in the presence of NE. Importantly, in the Skov3-ip1 restraint stress orthotopic model, silencing PTGS2 abrogated stress mediated effects and decreased tumor burden by 70% compared to control siRNA with restraint stress.

Conclusion Increased adrenergic stimulation results in a pro-inflammatory milieu mediated by prostaglandins that drives tumor progression and metastasis in ovarian cancer.

Citation Format: Archana S. Nagaraja, Piotr Dorniak, Nouara Sadaoui, Guillermo Armaiz-Pena, Behrouz Zand, Sherry Y. Wu, Julie K. Allen, Rajesha Rupaimoole, Cristian Rodriguez-Aguayo, Sunila Pradeep, Lin Tan, Rebecca A. Previs, Jean M. Hansen, Peiying Yang, Garbiel Lopez-Berestein, Susan K. Lutgendorf, Steve Cole, Anil K. Sood. Sustained adrenergic signaling activates pro-inflammatory prostaglandin network in ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3368. doi:10.1158/1538-7445.AM2015-3368

Other Article in This Open Access Journal on Ovarian Cancer Include

Beta-Blockers help in better survival in ovarian cancer

Ovarian Cancer Survival Increased 5 Months Overall With Beta Blockers – Study – The Speaker

Model mimicking clinical profile of patients with ovarian cancer @ Yale School of Medicine

Preclinical study identifies ‘master’ proto-oncogene that regulates stress-induced ovarian cancer metastasis | MD Anderson Cancer Center

Beta-Blockers help in better survival in ovarian cancer

Role of Primary Cilia in Ovarian Cancer

Dasatinib in Combination With Other Drugs for Advanced, Recurrent Ovarian Cancer

.

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New Generation of Platinated Compounds to Circumvent Resistance

Curator/Writer: Stephen J. Williams, Ph.D.

Resistance to chemotherapeutic drugs continues to be a major hurdle in the treatment of neoplastic disorders, irregardless if the drug is a member of the cytotoxic “older” drugs or the cytostatic “newer” personalized therapies like the tyrosine kinase inhibitors.  For the platinatum compounds such as cisplatin and carboplatin, which are mainstays in therapeutic regimens for ovarian and certain head and neck cancers, development of resistance is often regarded as the final blow, as new options for these diseases have been limited.

Although there are many mechanisms by which resistance to platinated compounds may develop the purpose of this posting is not to do an in-depth review of this area except to refer the reader to the book   Ovarian Cancer and just to summarize the well accepted mechanisms of cisplatin resistance including:

  • Decreased cellular cisplatin influx
  • Increased cellular cisplatin efflux
  • Increased cellular glutathione and subsequent conjugation, inactivation
  • Increased glutathione-S-transferase activity (GST) and subsequent inactivation, conjugation
  • Increased γ-GGT
  • Increased metallothionenes with subsequent conjugation, inactivation
  • Increased DNA repair: increased excision repair
  • DNA damage tolerance: loss of mismatch repair (MMR)
  • altered cell signaling activities and cell cycle protein expression

Williams, S.J., and Hamilton, T.C. Chemotherapeutic resistance in ovarian cancer. In: S.C. Rubin, and G.P. Sutton (eds.), Ovarian Cancer, pp.34-44. Lippincott, Wilkins, and Williams, New York, 2000.

Also for a great review on clinical platinum resistance by Drs. Maritn, Hamilton and Schilder please see the following Clinical Cancer Research link here.

This curation represents the scientific rationale for the development of a new class of platinated compounds which are meant to circumvent mechanisms of resistance, in this case the loss of mismatch repair (MMR) and increased tolerance to DNA damage.

An early step in the production of cytotoxicity by the important anticancer drug cisplatin and its analog carboplatin is the formation of intra- and inter-strand adducts with tumor cell DNA 1-3. This damage triggers a cascade of events, best characterized by activation of damage-sensing kinases (reviewed in 4), p53 stabilization, and induction of p53-related genes involved in apoptosis and cell cycle arrest, such as bax and the cyclin-dependent kinase inhibitor p21waf1/cip1/sdi1 (p21), respectively 5,6. DNA damage significantly induces p21 in various p53 wild-type tumor cell lines, including ovarian carcinoma cells, and this induction is responsible for the cell cycle arrest at G1/S and G2/M borders, allowing time for repair 7,8.  DNA lesions have the ability of  to result in an opening of chromatin structure, allowing for transcription factors to enter 56-58.  Therefore the anti-tumoral ability of cisplatin and other DNA damaging agents is correlated to their ability to bind to DNA and elicit responses, such as DNA breaks or DNA damage responses which ultimately lead to cell cycle arrest and apoptosis.  Therefore either repair of such lesions, the lack of recognition of such lesions, or the cellular tolerance of such lesions can lead to resistance of these agents.

resistmech2

Mechanisms of Cisplatin Sensitivity and Resistance. Red arrows show how a DNA lesion results in chemo-sensitivity while the beige arrow show common mechanisms of resistance including increased repair of the lesion, effects on expression patterns, and increased inactivation of the DNA damaging agent by conjugation reactions

 

 

 

 

 

 

 

 

 

 

 

 

 

 

mechPtresistance

 

 

Increased DNA Repair Mechanisms of Platinated Lesion Lead to ChemoResistance

 

DNA_repair_pathways

Description of Different Types of Cellular DNA Repair Pathways. Nucleotide Excision Repair is commonly up-regulated in highly cisplatin resistant cells

 

 

 

 

 

 

 

 

 

 

 

Loss of Mismatch Repair Can Lead to DNA Damage Tolerance

dnadamage tolerance

 

 

 

 

 

 

 

 

In the following Cancer Research paper Dr. Vaisman in the lab of Dr. Steve Chaney at North Carolina (and in collaboration with Dr. Tom Hamilton) describe how cisplatin resistance may arise from loss of mismatch repair and how oxaliplatin lesions are not recognized by the mismatch repair system.
Cancer Res. 1998 Aug 15;58(16):3579-85.

The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: correlation with replicative bypass of platinum-DNA adducts.

Abstract

Defects in mismatch repair are associated with cisplatin resistance, and several mechanisms have been proposed to explain this correlation. It is hypothesized that futile cycles of translesion synthesis past cisplatin-DNA adducts followed by removal of the newly synthesized DNA by an active mismatch repair system may lead to cell death. Thus, resistance to platinum-DNA adducts could arise through loss of the mismatch repair pathway. However, no direct link between mismatch repair status and replicative bypass ability has been reported. In this study, cytotoxicity and steady-state chain elongation assays indicate that hMLH1 or hMSH6 defects result in 1.5-4.8-fold increased cisplatin resistance and 2.5-6-fold increased replicative bypass of cisplatin adducts. Oxaliplatin adducts are not recognized by the mismatch repair complex, and no significant differences in bypass of oxaliplatin adducts in mismatch repair-proficient and -defective cells were found. Defects in hMSH3 did not alter sensitivity to, or replicative bypass of, either cisplatin or oxaliplatin adducts. These observations support the hypothesis that mismatch repair defects in hMutL alpha and hMutS alpha, but not in hMutS beta, contribute to increased net replicative bypass of cisplatin adducts and therefore to drug resistance by preventing futile cycles of translesion synthesis and mismatch correction.

 

 

The following are slides I had co-prepared with my mentor Dr. Thomas C. Hamilton, Ph.D. of Fox Chase Cancer Center on DNA Mismatch Repair, Oxaliplatin and Ovarina Cancer.

edinborough2mmrtranslesion1

 

 

 

 

 

 

Multiple Platinum Analogs of Cisplatin (like Oxaliplatin )Had Been Designed to be Sensitive in MMR Deficient Tumors

edinborough2diffptanalogs

 

 

 

 

 

 

mmroxaliplatin

 

 

 

 

 

 

edinborough2ptanalogsresist

 

 

 

 

 

 

edinborough2relresistptanalogsdifflines

 

 

 

 

 

 

edinborough2msimlmh2refract

 

 

 

 

 

 

edinborough2gogoxaliplatintrial

 

 

 

 

 

 

 

Please see below video on 2015 Nobel Laureates and their work to elucidate the celluar DNA repair mechanisms.

Clinical genetics expert Kenneth Offit gives an overview of Lynch syndrome, a genetic disorder that can cause colon (HNPCC) and other cancers by defects in the MSH2 DNA mismatch repair gene. (View Video)

 

 

References

  1. Johnson, S. W. et al. Relationship between platinum-DNA adduct formation, removal, and cytotoxicity in cisplatin sensitive and resistant human ovarian cancer cells. Cancer Res 54, 5911-5916 (1994).
  2. Eastman, A. The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. Pharmacology and Therapeutics 34, 155-166 (1987).
  3. Zhen, W. et al. Increased gene-specific repair of cisplatin interstrand cross-links in cisplatin-resistant human ovarian cancer cell lines. Molecular and Cellular Biology 12, 3689-3698 (1992).
  4. Durocher, D. & Jackson, S. P. DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell Biol 13, 225-231 (2001).
  5. el-Deiry, W. S. p21/p53, cellular growth control and genomic integrity. Curr Top Microbiol Immunol 227, 121-37 (1998).
  6. Ewen, M. E. & Miller, S. J. p53 and translational control. Biochim Biophys Acta 1242, 181-4 (1996).
  7. Gartel, A. L., Serfas, M. S. & Tyner, A. L. p21–negative regulator of the cell cycle. Proc Soc Exp Biol Med 213, 138-49 (1996).
  8. Chang, B. D. et al. p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene 19, 2165-70 (2000).
  9. Davies, N. P., Hardman, L. C. & Murray, V. The effect of chromatin structure on cisplatin damage in intact human cells. Nucleic Acids Res 28, 2954-2958 (2000).
  10. Vichi, P. et al. Cisplatin- and UV-damaged DNA lure the basal transcription factor TFIID/TBP. Embo J 16, 7444-7456 (1997).
  11. Xiao, G. et al. A DNA damage signal is required for p53 to activate gadd45. Cancer Res 60, 1711-9 (2000).

Other articles in this Open Access Journal on ChemoResistance Include:

Cancer Stem Cells as a Mechanism of Resistance

An alternative approach to overcoming the apoptotic resistance of pancreatic cancer

Mutation D538G – a novel mechanism conferring acquired Endocrine Resistance causes a change in the Estrogen Receptor and Treatment of Breast Cancer with Tamoxifen

Can IntraTumoral Heterogeneity Be Thought of as a Mechanism of Resistance?

Nitric Oxide Mitigates Sensitivity of Melanoma Cells to Cisplatin

Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

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