A Way to Kill Chemo-Resistant Ovarian Cancer Cells: Cut Down Their Protector

A recent study provides new insight into why ovarian cancer is often resistant to chemotherapy, as well as a potential way to improve its diagnosis and treatment.

Protein Data Base 3-D rendering of the Gelsolin protein. (Photo: Wikipedia)

Protein Data Base 3-D rendering of the gelsolin protein. (Photo: Wikipedia)

Ovarian cancer is the most lethal gynecological cancer, claiming the lives of more than 60% of women who are diagnosed with the disease. A study involving Ottawa and Taiwan researchers, published in the influential Proceedings of the National Academy of Sciences (PNAS), provides new insight into why ovarian cancer is often resistant to chemotherapy, as well as a potential way to improve its diagnosis and treatment.

It is estimated that 2,700 Canadian women will be diagnosed with ovarian cancer in 2014 and that 1,750 Canadian women will die from the disease, according to Ovarian Cancer Canada. This cancer is often diagnosed late and develops a resistance to chemotherapy.

tsang_ben

Dr. Ben Tsang

“What we’ve discovered will help clinicians to better treat women with ovarian cancer,” says Dr. Ben Tsang, senior scientist at the Ottawa Hospital Research Institute and professor at the University of Ottawa. “The key is understanding the role of a protein called “gelsolin.” With our colleagues from National Cheng Kung University in Taiwan, we found that an increased level of this protein is associated with aggressive forms of ovarian cancer that are more likely to be resistant to chemotherapy and lead to death.”

The researchers showed how gelsolin works at the molecular level to protect cancer cells against a widely used chemotherapy drug called “cisplatin.”

The findings are important because they will help clinicians to determine the most effective treatment plan based on the level of gelsolin. Work still needs to be done to determine exactly how much gelsolin indicates a cancer that is chemo-resistant and would require different treatment options.

In addition, this same protein that makes ovarian cancer cells resistant to chemotherapy can be used to overcome this treatment obstacle. By cutting gelsolin down to a specific fragment and putting it into chemo-resistant cancer cells, the international team discovered they could make these cells susceptible to the cancer-killing effects of cisplatin.

Shieh

Dr. Dar-Bin Shieh

“We believe this discovery is a promising avenue for developing a new therapy to reduce chemo-resistance in women with this deadly disease,” said Dr. Dar-Bin Shieh, collaborative partner from National Cheng Kung University of Taiwan. Shieh is currently leading the International Institute of Macromolecular Analysis and Nanomedicine Innovation (IMANI), which is focused on translating molecular discoveries to the clinic.

Based on 2009 estimates, approximately one in 72 Canadian women will develop ovarian cancer in her lifetime and one in 93 will die from it.

This study was supported by the Canadian Institutes of Health Research and the National Science Council of Taiwan.

Ottawa Hospital Research Institute
The Ottawa Hospital Research Institute is the research arm of The Ottawa Hospital and is an affiliated institute of the University of Ottawa, closely associated with its faculties of Medicine and Health Sciences. The Ottawa Hospital Research Institute includes more than 1,700 scientists, clinical investigators, graduate students, postdoctoral fellows and staff conducting research to improve the understanding, prevention, diagnosis and treatment of human disease. Research at Ottawa Hospital Research Institute is supported by The Ottawa Hospital Foundation.

University of Ottawa: A crossroads of cultures and ideas
The University of Ottawa is home to almost 50,000 students, faculty and staff, who live, work and study in both French and English. The campus is a crossroads of cultures and disciplines, where bold minds come together to inspire game-changing ideas. The University of Ottawa is one of Canada’s top 10 research universities — our professors and researchers explore new approaches to today’s challenges. One of a handful of Canadian universities ranked among the top 200 in the world, we attract exceptional thinkers and welcome diverse perspectives from across the globe.

National Cheng Kung University
National Cheng Kung University (NCKU) is a research-led comprehensive university in Tainan City, Taiwan. Since its establishment in 1931, NCKU has nurtured countless social elites and leaders under the trailblazing efforts of its former faculties and staffs. NCKU is one of the most prestigious universities in Taiwan, with a high reputation in science, engineering, medicine, management, planning and design. The university is a role model for the transformation of Taiwan’s higher-educational institutes, and is also an important pillar of the country’s economic and industrial structure.

Sources:

Stanford Researchers Create “Evolved” Protein That May Stop Breast & Ovarian Cancers From Spreading

 Early but promising tests in lab mice suggest that a bioengineered protein therapy, administered intravenously, may halt the spread of breast and ovarian cancers from their original tumor sites. Mice with ovarian cancer had a 90 percent reduction in metastatic nodules when treated with the engineered decoy protein. This approach might one day provide an alternative to, or supplement, chemotherapy.

A team of Stanford researchers has developed a protein therapy that disrupts the process that causes cancer cells to break away from the original tumor site, travel through the bloodstream and start aggressive new growths elsewhere in the body.

stanford metastasis_news

Drs. Jennifer Cochran and Amato Giaccia led a team of researchers who have developed an experimental therapy to treat metastatic cancer. (Photo: Rod Searcey)

This process, known as “metastasis,” can cause cancer to spread with deadly effect.

“The majority of patients who succumb to cancer fall prey to metastatic forms of the disease,” said Dr. Jennifer Cochran, an associate professor of bioengineering, who describes a new therapeutic approach in Nature Chemical Biology.

Today, doctors try to slow or stop metastasis with chemotherapy, but these treatments are unfortunately not very effective and have severe side effects.

The Stanford team seeks to stop metastasis, without side effects, by preventing two proteins – Axl and Gas6 – from interacting to initiate the spread of cancer.

Axl proteins stand like bristles on the surface of cancer cells, poised to receive biochemical signals from Gas6 proteins.

When two Gas6 proteins link with two Axls, the signals that are generated enable cancer cells to leave the original tumor site, migrate to other parts of the body, and form new cancer nodules.

To stop this process Cochran used protein engineering to create a harmless version of Axl that acts like a decoy. This decoy Axl latches on to Gas6 proteins in the bloodstream and prevents them from linking with and activating the Axls present on cancer cells.

In collaboration with Dr. Amato Giaccia, who leads the Radiation & Cancer Biology Program in the Stanford Cancer Center, the researchers gave intravenous treatments of this bioengineered decoy protein to mice with aggressive breast and ovarian cancers.

The mice in the breast cancer treatment group had 78 percent fewer metastatic nodules than the untreated mice. Mice with ovarian cancer had a 90 percent reduction in metastatic nodules when treated with the engineered decoy protein.

“This is a very promising therapy that appears to be effective and nontoxic in preclinical experiments,” Giaccia said. “It could open up a new approach to cancer treatment.”

Drs. Giaccia and Cochran are scientific advisors to Ruga Corporation, a biotechnology startup located in Palo Alto that has licensed this technology from Stanford. Further preclinical and animal tests must be done before determining whether this therapy is safe and effective in humans.

Professor, Molecular Neurobiology Laboratory,  Françoise Gilot-Salk Chair

Professor, Molecular Neurobiology Laboratory,
Françoise Gilot-Salk Chair, Salk Institute

Greg Lemke, of the Molecular Neurobiology Laboratory at the Salk Institute, called this “a prime example of what bioengineering can do” to open new therapeutic approaches to treat metastatic cancer.

“One of the remarkable things about this work is the binding affinity of the decoy protein,” said Lemke, a noted authority on Axl and Gas6 who was not part of the Stanford experiments.

“The decoy attaches to Gas6 up to a hundredfold more effectively than the natural Axl,” Lemke said. “It really sops up Gas6 and takes it out of action.”

Directed Evolution

The Stanford approach is grounded on the fact that all biological processes are driven by the interaction of proteins, the molecules that fit together in lock-and-key fashion to perform all the tasks required for living things to function.

In nature, proteins evolve over millions of years. But bioengineers have developed ways to accelerate the process of improving these tiny parts using technology called “directed evolution.” This particular application was the subject of the doctoral thesis of Mihalis Kariolis, a bioengineering graduate student in Cochran’s lab.

Using genetic manipulation, the Stanford team created millions of slightly different DNA sequences. Each DNA sequence coded for a different variant of Axl.

The researchers then used high-throughput screening to evaluate more than 10 million Axl variants. Their goal was to find the variant that bound most tightly to Gas6.

 (Video: Tim Saguinsin, Ricecooker Studios)

Kariolis made other tweaks to enable the bioengineered decoy to remain in the bloodstream longer and also to tighten its grip on Gas6, rendering the decoy interaction virtually irreversible.

Yu Rebecca Miao, a postdoctoral scholar in Giaccia’s lab, designed the testing in animals and worked with Kariolis to administer the decoy Axl to the lab mice. They also did comparison tests to show that sopping up Gas6 resulted in far fewer secondary cancer nodules.

Irimpan Mathews, a protein crystallography expert at SLAC National Accelerator Laboratory, joined the research effort to help the team better understand the binding mechanism between the Axl decoy and Gas6.

Protein crystallography captures the interaction of two proteins in a solid form, allowing researchers to take X-ray-like images of how the atoms in each protein bind together. These images showed molecular changes that allowed the bioengineered Axl decoy to bind Gas6 far more tightly than the natural Axl protein.

Next Steps

Years of work lie ahead to determine whether this protein therapy can be approved to treat cancer in humans. Bioprocess engineers must first scale up production of the Axl decoy to generate pure material for clinical tests. Clinical researchers must then perform additional animal tests in order to win approval for and to conduct human trials. These are expensive and time-consuming steps.

But these early, promising results suggest that the Stanford approach could become a nontoxic way to fight metastatic cancer.

Glenn Dranoff, M.D., a professor of medicine at Harvard Medical School and a leading researcher at the Dana-Farber Cancer Institute, reviewed an advance copy of the Stanford paper but was otherwise unconnected with the research. “It is a beautiful piece of biochemistry and has some nuances that make it particularly exciting,” Dranoff said, noting that tumors often have more than one way to ensure their survival and propagation.

Axl has two protein cousins, Mer and Tyro3, that can also promote metastasis. Mer and Tyro3 are also activated by Gas6.

“So one therapeutic decoy might potentially affect all three related proteins that are critical in cancer development and progression,” Dranoff said.

Erinn Rankin, a postdoctoral fellow in the Giaccia lab, carried out proof of principle experiments that paved the way for this study.

Other co-authors on the Nature Chemical Biology paper include Douglas Jones, a former doctoral student, and Shiven Kapur, a postdoctoral scholar, both of Cochran’s lab, who contributed to the protein engineering and structural characterization, respectively.

Cochran said Stanford’s support for interdisciplinary research made this work possible.

Stanford ChEM-H (Chemistry, Engineering & Medicine for Human Health) provided seed funds that allowed Cochran and Mathews to collaborate on protein structural studies.

The Stanford Wallace H. Coulter Translational Research Grant Program, which supports collaborations between engineers and medical researchers, supported the efforts of Cochran and Giaccia to apply cutting-edge bioengineering techniques to this critical medical need.

Sources:

 

Role For Gemcitabine As Second-line Chemotherapy in Recurrent Clear Cell Ovarian Cancer

In a recent 2014 retrospective analysis involving 72 recurrent ovarian clear cell patients who underwent second-line therapy at one of 20 Italian centers over a 16-year period, the researchers noted that a small subgroup of patients who received the drug gemcitabine (Gemzar®) appeared to have a higher rate of tumor response, as compared to women who were treated with topotecan (Hycamtin®) or pegylated liposomal doxorubicin (Doxil®).

Clear Cell Carcinoma of the Ovary

Clear Cell Carcinoma of the Ovary

In the July 2014 issue of Oncology, Italian researchers present an interesting retrospective analysis of patients with recurrent clear-cell ovarian cancer [1], a fairly chemoresistant subtype of ovarian cancer that can be difficult to treat.

This retrospective analysis included 72 recurrent ovarian clear cell patients (OCCC), who underwent second-line therapy at one of 20 Italian centers over a 16-year period (as part of the “Multicenter Italian Trial in Ovarian Cancer” or “MITO-9″).

In 56% of the OCCC patients, the clear cell histology was “pure,” meaning the predominant cell type identified within the primary tumor was classified as clear cell (i.e., a subtype of epithelial ovarian cancer) by a molecular pathologist. Twenty-five patients were platinum-resistant, 18 patients were platinum-sensitive with a platinum-free interval (PFI) of 6-to-12 months, and 29 patients had a PFI >12 months. Upon disease recurrence, 47% of patients were treated with platinum chemotherapy (e.g., carboplatin or cisplatin) based upon PFI.

The overall tumor response rate (RR) to the use of platinum drugs was 80%, with 55%, 100%, and 80% RRs in patients with PFIs of 6-to-12 months, >12 months, and >24 months, respectively. The RR to non-platinum drugs in resistant OCCC patients was 33%. Among the non-platinum drugs used in primary and secondary resistant cases, gemcitabine (Gemzar®), administered to 12 OCCC patients, produced higher anti-cancer activity (RR = 66%), as compared to topotecan (Hycamtin®) or liposomal doxorubicin (Doxil®) (number of patients = 31; RRs = 33% and 10%, respectively).

The Italian researchers concluded that the overall study results suggest that the treatment of recurrent OCCC, in general, should be based upon the duration of the patient’s PFI, as is customary in the treatment of other epithelial ovarian cancer subtypes. However, the data relating to the platinum-resistant OCCC patients evaluated in the Italian study suggest that gemcitabine (Gemzar®) was the drug that produced the greatest anti-cancer activity.

Notably, the results reported by the Italian researchers are consistent with the similar findings reported in a small number of previous studies involving an equally small number of recurrent OCCC patients. [2 - 5]

Maurie Markman, M.D.

Also appearing in the July 2014 Oncology issue is a commentary written by Maurie Markman, M.D., the President of the Medicine and Science unit of the Cancer Treatment Centers of America (CTCA).[6] Dr. Markman oversees the CTCA national clinical team, with a focus on the application of all clinical and translational research to patient care. In his commentary, Dr. Markman notes the importance of retrospective studies as a “long-established tradition in clinical cancer investigation.” Dr. Markman highlights the potential inportance of retrospective studies as noted below.

  • Single institutional data or large multicenter efforts examining past experiences can serve both as “hypothesis-generating” elements for a future prospective clinical study, an idea to be explored in a translational laboratory research project, and even as confirmation of the results of a reported study in a more heterogeneous patient population.
  • Retrospective analyses can provide critically relevant data in populations known to be poorly represented in cancer clinical trials and may identify adverse events potentially not recognized in the often highly homogenous groups of study participants.
  • The safety and the efficacy associated with longer observation periods and a more prolonged therapy than reported in many prospective clinical trials can be revealed through retrospective examinations of previously treated patients.

Within this context, Dr. Markman addresses the limitations of the Italian recurrent OCCC retrospective analyses cited above, but he also emphasizes the potential benefit of that study, as follows:

“Of course, it must be emphasized that the very limited sample size does not permit any definitive conclusions regarding the relative utility of any individual strategy, including providing a truly meaningful ‘objective response rate’. However, recognizing the rarity of this specific malignant condition (72 total [OCCC] patients identified in a period of 16 years at 20 centers), this retrospective experience will likely be of some value to individual oncologists needing to consider potential therapeutic options for a patient with recurrent clear-cell ovarian cancer. Further, in the event a multi-institutional prospective trial is ultimately undertaken in this most uncommon clinical setting, the results of this retrospective analysis should surely help to inform the planned study design.” [emphasis added]

At Libby’s H*O*P*E*, we generally recommend that recurrent OCCC patients speak to their doctor about the potential benefits (and limitations) associated with (i) molecular/genomic tumor profiling,  and (ii) chemosensistivity and resistance assay (CSRA) testing. The use of both forms of tumor testing may provide a recurrent OCCC patient and her doctor(s) with additional insights related to specific treatment options. In the event that neither form of tumor testing is possible, the results from the Italian study discussed above suggest that the use of gemcitabine (Gemzar®) to treat recurrent OCCC should be, at a minimum, considered by a recurrent OCCC patient and her doctor.

In addition, we strongly recommend that a newly-diagnosed or recurrent OCCC patient should consider the drugs being currently evaluated, as of this writing, in open OCCC patient-dedicated clinical trials, including as temsirolimus (Torisel®) [7], sunitinib (Sutent®) [8], ENMD-2076 [9], and dasatinib (Sprycel®) [10].

References:

1./ Esposito F et al. Second-line chemotherapy in recurrent clear cell ovarian cancer: Results from the Multicenter Italian Trials in Ovarian Cancer (MITO-9). Oncology 2014;86:351-358. PubMed PMID:24942520.

2./ Yoshino K, et al. Salvage chemotherapy for recurrent or persistent clear cell carcinoma of the ovary: a single-institution experience for a series of 20 patients. Int J Clin Oncol. 2013 Feb;18(1):148-53. doi: 10.1007/s10147-011-0357-5. Epub 2011 Dec 10. PubMed PMID: 22160560.

3./ Komiyama S et al. A heavily pretreated patient with recurrent clear cell adenocarcinoma of the ovary in whom carcinomatous peritonitis was controlled successfully by salvage therapy with gemcitabine. Arch Gynecol Obstet. 2008 Dec;278(6):565-8. Epub 2007 Jun 19. Erratum in: Arch Gynecol Obstet. 2009 Feb;279(2):271. Komiyama, Shin [corrected to Komiyama, Shin-ichi]. PubMed PMID: 17576588.

4./ Ferrandina G et al. A case of drug resistant clear cell ovarian cancer showing responsiveness to gemcitabine at first administration and at re-challenge. Cancer Chemother Pharmacol. 2007 Aug;60(3):459-61. Epub 2007 Apr 11. PubMed PMID: 17429624.

5./ Crotzer DR et al. Lack of effective systemic therapy for recurrent clear cell carcinoma of the ovary. Gynecol Oncol. 2007 May;105(2):404-8. Epub 2007 Feb 9. PubMed PMID: 17292461.

6./ Markman M. A Unique Role for Retrospective Studies in Clinical Oncology. Oncology. 2014;86(5-6):350. doi: 10.1159/000360911. Epub 2014 Jun 12. PubMed PMID:24942408.

7./ A Phase II Evaluation of Temsirolimus (CCI-779) (NCI Supplied Agent: NSC# 683864,) in Combination With Carboplatin and Paclitaxel Followed by Temsirolimus (CCI-779) Consolidation as First-Line Therapy in the Treatment of Stage III-IV Clear Cell Carcinoma of the Ovary. ClinicalTrials.gov Identifier: NCT01196429.

8./ A Phase II Evaluation of the Efficacy of Sunitinib® in Patients With Recurrent Ovarian Clear Cell Carcinoma. ClinicalTrials.gov Identifier: NCT01824615.

9./ A Phase II Study of Oral ENMD-2076 Administered to Patients With Ovarian Clear Cell Carcinomas. ClinicalTrials.gov Identifier: NCT01914510.

10./ A Phase II Trial of DCTD-Sponsored Dasatinib (NSC #732517) in Recurrent/Persistent Ovary, Fallopian Tube, Primary Peritoneal, and Endometrial Clear Cell Carcinoma Characterized for the Retention or Loss of BAF250a Expression. ClinicalTrials.gov Identifier: NCT02059265.

 

 

Dana Farber Webchat: The Latest in Ovarian Cancer Treatment & Research

The latest developments in ovarian cancer treatment and research are addressed in the video below via a Dana-Farber Cancer Institute webchat that was conducted on September 16, 2014.

The Susan F. Smith Center for Women’s Cancers at the Dana-Farber Cancer Institute conducted a live video webchat panel with Ursula Matulonis, M.D., medical director of the Gynecologic Oncology Program, and gynecologic oncologists Panos Konstantinopoulos, M.D., Ph.D., and Susana Campos, M.D., MPH. The live webchat was held on September 16, 2014.

The general webchat topics addressed by the Dana-Farber doctors are listed below. For your convenience, we also provided the approximate video start time associated with each discussion topic. The entire video runs 49 minutes and 20 seconds.

  • Various types/subtypes of ovarian cancer and treatment differences. [1:40 minutes]
  • CA-125 and other ovarian cancer biomarkers. [5:10 minutes]
  • Areas of ongoing ovarian cancer research. [9:28 minutes]
  • Ovarian cancer treatment alternatives to standard of care chemotherapy. [13:55 minutes]
  • PARP Inhibitors & Immunotherapy. [15:03 minutes]
  • Mechanisms to reverse platinum drug resistance. [17:15 minutes]
  • Correlation between ovarian cancer and HPV (Human papillomavirus). [19:30 minutes]
  • The use of clinical trials for the treatment of ovarian cancer. [19:43 minutes]
  • Stage 1 ovarian cancer prognosis. [21:47 minutes]
  • Gene mutations related to hereditary ovarian cancer risk. [22:55 minutes]
  • Treatment options for platinum drug refractory/resistant ovarian cancer. [25:27 minutes]
  • Treatment of BRCA gene-mutated ovarian cancer patients. [27:50 minutes]
  • Ovarian cancer prevention. [30:18 minutes]
  • Promising treatments for ovarian clear cell cancer. [31:43 minutes]
  • Proper nutrition during and after ovarian cancer treatment. [33:47 minutes]
  • Symptoms associated with an ovarian cancer recurrence. [35:06 minutes]
  • Ovarian neuroendocrine cancer. [36:16 minutes]
  • Small-cell ovarian cancer. [39:22 minutes]
  • Origin of ovarian cancer. [42:41 minutes]
  • Treatment options for isolated or limited recurrent ovarian cancer tumors/lesions. [45:26 minutes]
  • Closing: Most Exciting Ovarian Cancer Developments. [47:07 minutes]

 

Improved Survival of Ovarian Cancer Patients Receiving Treatment Guided by Comprehensive Tumor Profiling

A preliminary report from the Caris Registry™ demonstrated significantly longer post-profiling survival in patients with ovarian, Fallopian tube or primary peritoneal cancer who were given treatments that their tumor profile showed were likely to benefit.

Data from an ovarian cancer registry presented at the 2014 European Society for Gynaecological Oncology (ESGO) annual meeting reinforce comprehensive tumor profiling as a “game changer” for oncologists.

The preliminary report from the Caris Registry™ demonstrated significantly longer post-profiling survival in patients with ovarian, Fallopian tube, or primary peritoneal cancer who were given treatments that their tumor profile showed were likely to benefit them, as compared with patients who were treated with drugs that profiling suggested would be less effective. Data[1] revealed that patients whose treatment was guided by tumor profiling had a 46% lower risk of death (Hazard Ratio = 0.54, p value = 0.0018).

The comprehensive tumor profiling service used in the study measures a broad range of cancer “biomarkers” (proteins, genes or other molecules that affect how cancer cells grow, multiply and respond to therapies) and interprets the results to identify treatments most likely to be of benefit and help eliminate those that are less likely to benefit the patient. The results allow oncologists to better determine appropriate treatments for each patient, based on the individual makeup of their cancer rather than the site of the tumor.

Data from earlier studies show that comprehensive tumor profiling consistently identifies biomarkers linked to specific treatments in over 90% of patients[2], and that clinicians change their intended treatment decision based on profiling results in over 80% of cases[3].  Across a range of cancer types, tumor profiling-guided treatment has been shown to benefit patients[4] and improve outcomes when compared to unguided treatment[5].  The ESGO data demonstrate that for many ovarian cancer patients who have run out of options, comprehensive tumor profiling consistently offers oncologists actionable insights to help choose a patient’s next treatment and can improve patient outcomes.

Professor Hani Gabra

Professor Hani Gabra

Professor Hani Gabra, author of the ESGO publication and Director, Ovarian Cancer Action Research Centre at Imperial College London, said:

“The data presented at ESGO this year further support the use of comprehensive tumor profiling. It offers new options to patients whose cancers are difficult to treat or rare, or who have exhausted standard treatment options. I’m extremely excited to see this breadth of research on a global platform and I am hopeful that profiling will be rapidly adopted in clinical practice in Europe.”

Gilda Witte, CEO of Ovarian Cancer Action

Gilda Witte, CEO of Ovarian Cancer Action

Gilda Witte, Chief Executive of Ovarian Cancer Action, stated:

“In order to improve the outlook for women with ovarian cancer, we need to know much more about types of tumors, and tumor profiling is becoming paramount in this area. We are hugely impressed that Caris is investing in research to provide information on ovarian tumors and we hope that this potentially leads to a breakthrough in treatment which may subsequently impact survivorship.”

Andreas Voss

Andreas Voss, VP of Medical & Clinical Affairs, Caris Life Sciences

Andreas Voss, Vice President, Medical and Clinical Affairs, Caris Life Sciences said:

“Comprehensive tumor profiling is a hot topic this year. It is becoming increasingly clear that the best approach to tumor profiling is to use a variety of methods to test for mutations, gene expression levels, and protein biomarkers. These combined analyses provide a comprehensive report and actionable treatment options for oncologists. Caris Molecular Intelligence™ remains the world’s most advanced commercial tumor profiling service – we are proud to be working with leading oncologists worldwide to bring the benefits of tumor profiling to cancer patients.”

Caris Molecular Intelligence™ is not yet formally reimbursed across Europe but it is available to purchase in all European markets. Individual insurance companies, clinics and organizations in some countries have agreed to reimburse the service on application. Caris Life Sciences is dedicated to working to ensure the service is reimbursed across Europe.

References:

1. Poster by Oliver KE et al. Tumour molecular profile-directed treatment is associated with improved survival in recurrent epithelial ovarian cancer. ESGO 2014. See also Oliver KE et al. The impact of tumor molecular profile-directed treatment on survival in recurrent ovarian cancer. J Clin Oncol 32:5s, 2014 (suppl; abstr 5591).

2. Astsaturov IA et al. Profiling of 1,250 neuroendocrine tumors identifies multiple potential drug targets. J Clin Oncol 32, 2014 (Suppl 3; Abstr 214).

3. Epelbaum R et al. Molecular Profiling (MP)-Selected Therapy for the Treatment of Patients with Advanced Pancreaticobiliary Cancer (PBC), 2013 ASCO GI Symposium. Jan 2013. (Abstract Number 195).

4. Von Hoff D et al., Pilot Study Using Molecular Profiling of Patients’ Tumors to Find Potential Targets and Select Treatments for Their Refractory Cancers, J Clin Oncol. Nov 20;28(33)2010:4877-83. Compare Doroshow JH. Selecting systemic cancer therapy one patient at a time: is there a role for molecular profiling of individual patients with advanced solid tumors? J Clin Oncol. 2010 Nov 20;28(33):4869-71. doi: 10.1200/JCO.2010.31.1472. Epub 2010 Oct 4. [PMID: 20921466].

5. Tsimberidou AM et al., Personalized Medicine in a Phase I Clinical Trials Program: The MD Anderson Cancer Center Initiative. Clin Cancer Res 18:6373-6383.

About Caris Life Sciences and Caris Molecular Intelligence™

Caris Life Sciences is a leading biosciences company focused on fulfilling the promise of precision medicine. Caris Molecular Intelligence™, the industry’s first and largest tumor profiling service, provides oncologists with the most potentially clinically actionable treatment options available to personalize care today. Using a variety of advanced and clinically validated technologies, which assess relevant biological changes in each patient’s tumor, Caris Molecular Intelligence correlates biomarker data generated from a tumor with biomarker/drug associations derived from the cancer clinical literature. The company is also developing a series of blood tests based on its proprietary Carisome® TOP™ platform, a revolutionary blood-based testing technology for diagnosis, prognosis, and theranosis of cancer and other complex diseases. Headquartered in Irving, Texas, Caris Life Sciences offers services throughout Europe, the U.S., Australia, and other international markets. To learn more, please visit http://www.carislifesciences.eu.

Source:  Improved Survival of Ovarian Cancer Patients Receiving Treatment Guided by Comprehensive Tumor Profiling, Caris Life Sciences Press Release, dated September 11, 2014 (with editorial changes)

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WIH Researchers Examine Role of Hormone HE4 in Patient Responses to Ovarian Cancer Treatment

Researchers at Women & Infants’ Hospital of Rhode Island recently published the results of an investigation into the role of hormone HE4 in patient responses to ovarian cancer treatment.

Researchers at Women & Infants’ Hospital of Rhode Island recently published the results of an investigation into how we might better tailor therapy for ovarian cancer.

The work comes out of the molecular therapeutic laboratory directed by Richard G. Moore, M.D., of Women & Infants’ Program in Women’s Oncology. Entitled “HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation,” the research was recently published in the international science journal Scientific Reports, a Nature publishing group.

The goal of the study was to investigate the role of the hormone HE4 (Human epididymis protein 4) in modulating ovarian cancer’s response to hormones and hormonal therapies. HE4 is a biomarker that is elevated in ovarian cancer and is known to play a role in resistance to chemotherapy.

Richard G. Moore, M.D.

Richard G. Moore, M.D.

“There is little known about the biologic functions of HE4 but we did know that there were hormonal responsive elements within the promoter region of the HE4 gene, which regulates gene expression. For this reason, we hypothesized that steroid hormones could influence expression of HE4 in ovarian cancer,” Moore explains.

The study resulted in multiple findings:

  • Hormonal therapies like tamoxifen (Nolvadex) and fulvestrant (Faslodex) are effective because they bind the estrogen receptor. If cells have less estrogen receptor expression, these drugs can’t do their job. This, the researchers believe, is due to epigenetic modifications which modify the DNA structure but not the DNA sequence itself. Overexpression led to the epigenetic modification known as decreased DNA methylation in cell culture and in human tissue samples.
  • Treatment of ovarian cancer cells with tamoxifen and fulvestrant all cause HE4 to translocate to the cell nucleus, where it can then effect further gene expression in cancer cells.
  • Using the drug ivermectin (broad-spectrum antiparasitic agent), the researchers were able to inhibit the protein import in-4, which then inhibited HE4 from translocating to the nucleus. If HE4 can’t enter the nucleus, it cannot affect gene expression. The ability to block HE4 from entering the nucleus restored sensitivity to hormonal therapy.

“We are not certain but believe this might mean there could be a subset of women whose tumors are more likely to respond to hormonal therapy. Moreover, we might be able to eventually identify which tumors these are and target treatment,” Moore says.

Dr. Moore’s lab will continue to investigate the expression of estrogen receptors in both primary and recurrent ovarian cancers and how that relates to HE4 expression. In addition, Dr. Moore and other researchers will investigate how importin inhibitors may play a role in addressing chemoresistance to standard therapeutics, particularly in HE4 overexpressing tumors.

About Women & Infants Hospital

Women & Infants’ Hospital of Rhode Island, a Care New England hospital, is one of the nation’s leading specialty hospitals for women and newborns. The primary teaching affiliate of The Warren Alpert Medical School of Brown University for obstetrics, gynecology and newborn pediatrics, as well as a number of specialized programs in women’s medicine, Women & Infants’ is the eighth largest stand-alone obstetrical service in the country with nearly 8,400 deliveries per year.In 2009, Women & Infants opened the country’s largest, single-family room neonatal intensive care unit.

New England’s premier hospital for women and newborns, Women & Infants’ and Brown offer fellowship programs in gynecologic oncology, maternal-fetal medicine, urogynecology and reconstructive pelvic surgery, women’s mental health, neonatal-perinatal medicine, pediatric and perinatal pathology, gynecologic pathology and cytopathology, and reproductive endocrinology and infertility. It is home to the nation’s only mother-baby perinatal psychiatric partial hospital, as well as the nation’s only fellowship program in obstetric medicine.

Women & Infants’ Hospital has been designated as a Breast Center of Excellence from the American College of Radiography; a Center for In Vitro Maturation Excellence by SAGE In Vitro Fertilization; a Center of Biomedical Research Excellence by the National Institutes of Health; and a Neonatal Resource Services Center of Excellence. It is one of the largest and most prestigious research facilities in high risk and normal obstetrics, gynecology and newborn pediatrics in the nation, and is a member of the National Cancer Institute’s Gynecologic Oncology Group and the National Institutes of Health’s Pelvic Floor Disorders Network.

Sources:

  • Lokich E et al. “HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation.” Sci Rep. 2014 Jun 30;4:5500. doi: 10.1038/srep05500. [PMID:24975515] [PMCID:PMC4074789]

Related Posts:

  • Small Phase II Study Tests the Use of Fulvestrant in the Treatment of Recurrent Epithelial Ovarian Cancer (March 15, 2009).
  • European Researchers Find Estrogen Receptor Gene Amplification Occurs Rarely in Ovarian Cancer (February 24, 2009).
  • Working Smarter, Not Harder: Use of Anti-Estrogen Therapy to Battle Recurrent Ovarian Cancer (August 18, 2008).

SU2C Announces the Formation of a New Translational Research Ovarian Cancer “Dream Team”

Ovarian Cancer Community Joins Forces to Fight Deadliest Gynecologic Cancer. The New Stand Up To Cancer Dream Team Will Launch in 2015.

The Ovarian Cancer Research Fund, The Ovarian Cancer National Alliance, and the National Ovarian Cancer Coalition Team Up to Fund New Translational Research Ovarian Cancer “Dream Team.”

 

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A groundbreaking collaboration is underway among three national ovarian cancer organizations: Ovarian Cancer Research Fund (OCRF), Ovarian Cancer National Alliance (OCNA), and National Ovarian Cancer Coalition (NOCC). In partnership with Stand Up To Cancer (SU2C), this group will fund a new Ovarian Cancer Dream Team dedicated to piloting leading-edge, ovarian cancer research that will help patients and save lives.

This partnership was announced tonight by actor Pierce Brosnan on the Stand Up To Cancer’s biennial telecast, and in recognition of National Ovarian Cancer Awareness Month. The SU2C-OCRF-OCNA-NOCC Translational Research Dream Team grant will provide funding, over a three-year period, for research associated with this insidious disease.

Ovarian cancer is the deadliest of all the gynecologic cancers. Almost 22,000 American women will be diagnosed with ovarian cancer in 2014, and more than 14,000 women will lose their lives to the disease. By collaborating to fund an Ovarian Cancer Dream Team, OCRF, OCNA and NOCC, with SU2C, will further research in the field that can lead to new treatments and improved patient outcomes.

Later this month, SU2C, through its science partner the American Association for Cancer Research (AACR), will issue a “Call for Ideas” from researchers and scientists worldwide. The selected Dream Team will be announced next spring, with research beginning in July 2015.

OCRF“Ovarian Cancer Research Fund has been the leading nonprofit funder of ovarian cancer research for years, and this new collaboration is a wonderful way to mark our 20th anniversary,” said Audra Moran, CEO of Ovarian Cancer Research Fund. “We are excited that the Dream Team grant will continue our long tradition of supporting the most innovative research in the field, while providing scientists with a vital new source of financial support.”

OCNA1Calaneet Balas, CEO of the Ovarian Cancer National Alliance, said: “I am so thrilled that our three organizations are coming together to fight the disease we all care so much about. I believe the Ovarian Cancer Dream Team will be paradigm-shifting for our community, and I cannot wait to see what comes from this new initiative. We’re proud of the work the Alliance has done to secure federal research funding on behalf of all women, but the Dream Team gives us new opportunities for collaboration and innovation.”

NOCC - Logo“We are both proud and excited to join in supporting the Ovarian Cancer Dream Team, the first-ever collaboration of such efforts,” said David Barley, CEO of the National Ovarian Cancer Coalition. “We are looking forward to being instrumental in furthering ovarian cancer research. The impacts on families and communities continue to make ovarian cancer “More Than a Woman’s Disease®.” By working together we hope to make a difference in the lives of everyone we touch.”

About the Ovarian Cancer Research Fund
The Ovarian Cancer Research Fund (OCRF), founded in 1994, is the oldest and largest charity in the United States funding ovarian cancer research, and ranks third in overall ovarian cancer research funding only after the National Cancer Institute (NCI) and the U.S. Department of Defense (DOD). Its mission is to fund scientific research that leads to more effective identification, treatment, and ultimately a cure for ovarian cancer, as well as related educational and support initiatives. OCRF has invested nearly $60 million in ovarian cancer research through 217 grants to scientists at 65 leading medical centers in the United States. OCRF continues to take the lead in funding the best and most promising ovarian cancer research while supporting women and their loved ones affected by this terrible disease in our quest to end it. For more information, please visit www.ocrf.org.

About the Ovarian Cancer National Alliance
The Ovarian Cancer National Alliance is a powerful voice for everyone touched by ovarian cancer. We connect survivors, women at risk, caregivers, and health providers with the information and resources they need. We ensure that ovarian cancer is a priority for lawmakers and agencies in Washington, DC, and throughout the country. We help our community raise their voices on behalf of every life that has been affected by this disease. For more information, please visit: www.ovariancancer.org

About the National Ovarian Cancer Coalition
Since its inception in 1995, the National Ovarian Cancer Coalition (NOCC) has been committed to raising awareness, promoting education, and funding research in support of women, families, and communities touched by ovarian cancer. NOCC is well-established as an important national advocate for patients and families struggling with ovarian cancer. NOCC remains steadfast in its mission to save lives by fighting tirelessly to prevent and cure ovarian cancer, and to improve the quality of life for survivors. For more information, please visit: www.ovarian.org.

About Stand Up To Cancer
Stand Up To Cancer (SU2C) raises funds to accelerate the pace of research to get new therapies to patients quickly and save lives now. SU2C, a program of the Entertainment Industry Foundation (EIF) and a 501(c)(3) charitable organization, was established in 2008 by film and media leaders who utilize the industry’s resources to engage the public in supporting a new, collaborative model of cancer research, and to increase awareness about cancer prevention as well as progress being made in the fight against the disease. For more information, please visit: www.standup2cancer.org