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:

 

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]

 

Dana-Farber Oncologists Differ Widely on the Use of Multiplex Tumor Genomic Testing

A new study by researchers at the Dana-Farber Cancer Institute suggests that not all doctors are ready to embrace tests that may identify hundreds of genomic changes in a patient’s tumor sample for the purpose of determining appropriate treatment.

Many cancer researchers believe that cutting-edge advances in genomics will pave the way for personalized or “precision” cancer medicine for all patients in the near future. A new study by researchers at the Dana-Farber Cancer Institute, however, suggest that not all doctors are ready to embrace tests that look for hundreds of genomic changes in a patient’s tumor sample, while others plan to offer this type of cancer genomic tumor testing to most of their patients. The study findings were published recently in the Journal of Clinical Oncology [1], along with an accompanying editorial. [2]

The wide variation in attitudes was in part determined by physicians’ “genomic confidence.” Physicians who had a lot of confidence in their ability to use and explain genomic findings were more likely to want to prescribe the test and consider using test results when making treatment recommendations. Other physicians had lower levels of genomic confidence and were more reluctant to offer such testing. These findings are particularly interesting because the survey was carried out at the Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC), which has a comprehensive research program. The DF/BWCC research program allows all consenting patients to have genomic tumor testing, which is capable of finding gene mutations and other DNA alternations that drive a patient’s cancer. In some cases, the genomic tumor profiles identify “druggable” targets that may allow doctors to use specific drugs known to be effective against particular gene mutations or alterations.

The researchers were perplexed by another key study survey finding: 42 percent of responding oncologists approved of telling patients about genomic tumor test results even when their significance for the patient’s outlook and treatment is uncertain. This issue comes with the growing use of predictive multiplex genomic testing, which can identify tens or hundreds of gene mutations simultaneously and often detects rare DNA variants that may or may not be relevant to the treatment of an individual’s cancer.

“Some oncologists said we shouldn’t return these results to the patient, and others say ‘of course we should give them to the patient’,” said Stacy W. Gray, M.D., AM, of Dana-Farber, first author of the report. “I think the fact that we found so much variation in physicians’ confidence about their ability to use genetic data at a tertiary care, National Cancer Institute-designated Comprehensive Cancer Center makes us pause and wonder about how confident physicians in the community are about dealing with this,” she said. “It begs the question at a national level, how are we going to make sure that this technology for cancer care is adequately delivered?”

The study survey was conducted in 2011 and early 2012 as a baseline assessment of physicians’ attitudes prior to the rollout of the genomic tumor testing project referred to as “Profile” (which formerly utilized a technology platform called “OncoMap“) at DF/BWCC.

For purposes of the study, a total of 160 Dana-Farber adult cancer physicians – including medical oncologists (43%), surgeons (29%), and radiation oncologists (19%) – participated in the survey. They were asked about their current use of multiplex tumor genomic testing, their attitudes about multiplex testing, and their confidence in the ability to understand and use genomic data. The survey did not include a direct test of the physicians’ knowledge.

Among the many intriguing findings of this study, a wide variability in interest in multiplex tumor genomic testing was identified—25% of respondents anticipated testing more than 90% of their patients, whereas 17% of respondents anticipated testing 10% or less. Beliefs related to the potential value of multiplex tumor genomic testing were largely positive; most expressed belief that this form of testing would increase treatment (73%) and research options (90%) for patients, as well as both physician (80%) and patient satisfaction (80%).

Despite the foregoing, less than 50% of the physicians planned to view the multiplex tumor genomic testing results routinely. Moreover, the majority of respondents planned only to “rarely” or “sometimes” use the clinically relevant results (58%), called “Tier 1” by the study authors, and potentially actionable results (88%), called “Tier 2,” to assist them in the treatment of patients. However, the respondents more often indicated that results of multiplex tumor genomic tests should be shared with patients, particularly findings revealing the presence of a Tier 1 (clinically relevant) genomic variant—87% believed that these findings should be discussed—versus a Tier 2 (potentially actionable) genomic variant (50%), or a Tier 3 (uncertain significance) genomic variant (40%). A substantial minority (39%) also disagreed with a Dana-Farber Cancer Institute policy prohibiting the disclosure of Tier 3 genomic variants to patients.

Interestingly, despite limited exposure to routine genomic tests for a large portion of the respondents, the stated “genomic confidence” of participating physicians was quite high. The majority of participants reported that they were “somewhat” or “very” confident in their (i) knowledge of genomics (78%), (ii) ability to explain genomics (86%), and (iii) ability to use genomic results to guide treatment (74%); however, a substantial minority of the Dana-Farber physicians (28%) reported genomic confidence of “not very” or “not at all confident.”

Based upon the study survey findings, Dr. Gray and her colleagues conclude that there is “little consensus” on how physicians plan to use multiplex tumor genomic testing for personalized cancer care, and they suggest the need for evidence-based guidelines to help doctors determine when testing is indicated.

“I think one of the strengths of this study is that its information comes from an institution where ‘precision cancer medicine’ is available to everyone,” commented Barrett Rollins, M.D., Ph.D., Dana-Farber’s Chief Scientific Officer and a co-author of the paper. “It highlights the fact there’s a lot of work to be done before this can be considered a standard approach in oncology.”

The senior author of the study is Jane Weeks, M.D., MSc, of Dana-Farber; additional authors include Angel Cronin, MS, of Dana-Farber and Katherine Hicks-Courant, BA, of the University of Massachusetts Medical School.

The research was supported by the Dana-Farber Cancer Institute. Dr. Gray also receives support from the American Cancer Society (120529-MRSG-11-006-01-CPPB) and the National Human Genome Research Institute (U01HG006492)

Pursuant to a new phase of Profile, initiated by Dana-Farber in 2013, a more advanced technology platform (called “OncoPanel“) utilizes “massively parallel” or “next-generation” sequencing to read the genetic code of approximately 300 genes in each patient’s tumor sample. “Massively parallel” refers to the technology’s capacity for sequencing large numbers of genes simultaneously. The 300 genes evaluated in connection with the OncoPanel were chosen because they have been implicated in a variety of cancers.

In addition to the complete DNA sequencing of more than 300 genomic regions to detect known and unknown cancer-related mutations, the OncoPanel technology can also examine those regions for gains and losses of DNA sequences and rearrangements of DNA on chromosomes. The results are entered into a database for research purposes, but, if a patient agrees, the clinically important findings can also be returned to their doctor for use in the clinic.

The OncoPanel advanced sequencing platform is an important update to Dana-Farber’s original OncoMap platform. OncoPanel can detect not only commonly known gene mutations, but also other critical types of cancer-related DNA alterations not previously identified. In contrast, OncoMap was limited to screening for known cancer-related gene mutations. The OncoPanel testing is done at the Center for Advanced Molecular Diagnostics, a CLIA-certified laboratory operated by the Department of Pathology at Brigham and Women’s Hospital.

References:

1./ Gray SW, et al. Original Reports – Health Services and OutcomesPhysicians’ Attitudes About Multiplex Tumor Genomic TestingJ. Clin. Oncol., published online before print on March 24, 2014, doi:10.1200/JCO.2013.52.4298.

2./ Hall MJ. Conflicted Confidence: Academic Oncologists’ Views on Multiplex Tumor Genomic Testing. J. Clin. Oncol. Editorial, published online before print March 24, 2014, doi:10.1200/JCO.2013.54.8016

 

ENMD-2076 Monotherapy Demonstrates Anti-Cancer Activity in Recurrent, Platinum-Resistant Ovarian Clear Cell Carcinoma

An Aurora A/angiogenic kinase inhibitor named “ENMD-2076” demonstrated anti-cancer activity in recurrent, platinum-resistant epithelial ovarian cancer patients, including three patients with a difficult-to-treat subtype of the disease referred to as “clear cell carcinoma.”

An Aurora A/angiogenic kinase inhibitor named “ENMD-2076” demonstrated anti-cancer activity in recurrent, platinum-resistant epithelial ovarian cancer patients, including three patients with a difficult-to-treat subtype of the disease referred to as “clear cell carcinoma.” The trial drug results were reported in connection with a phase II clinical trial testing of ENMD-2076. The findings associated with ENMD-2076 were published in the January 2013 edition of the European Journal of Cancer.

ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers.

The phase II trial was an open-label, single-arm Phase II study of single agent ENMD-2076 taken daily (orally). The study enrolled 64 patients, and the progression-free survival (PFS) rate at 6 months was 22%, with a median time-to-progression of 3.6 months. The median number of prior treatment regimens per patient was two. The most common adverse events were fatigue, hypertension and diarrhea, with the most significant events being hypertension and fatigue. Unfortunately, none of the markers of mitotic index or angiogenesis evaluated in the archival tissue samples obtained were predictive of greater benefit or resistance to ENMD-2076 treatment.

Based on the foregoing results, the clinical investigators concluded that ENMD-2076 possesses anti-cancer activity in recurrent, platinum-resistant ovarian cancer, and they observed  toxicities were similar to other protein kinase inhibitors. The clinical investigators also noted that additional studies with ENMD-2076 are warranted, especially in combination with active chemotherapeutic agents in platinum-resistant patients. The investigators added that further work to determine appropriate biomarkers for ENMD-2076 should be incorporated into new clinical studies.

The co-authors of the article include clinical investigators from the Memorial Sloan-Kettering Cancer Center, Indiana University Simon Cancer Center, University of Colorado, and University of Chicago in the U.S., as well as the Princess Margaret Hospital and Campbell Family Institute for Cancer Research in Toronto, Canada.

Ursula Matulonis, M.D., Medical Director, Gynecologic Oncology, Dana-Farber Cancer Institute

Ursula A. Matulonis, M.D., Medical Director, Gynecologic Oncology, Dana-Farber Cancer Institute

Lead study author Dr. Ursula A. Matulonis, who is the medical director of Gynecologic Oncology at the Dana-Farber Cancer Institute, commented on the publication as follows:

Epithelial ovarian cancer represents the 4th leading cause of cancer deaths among women in the United States. There is unmet medical needs to develop new drugs with fewer side effects and/or better efficacy to improve the quality and duration of life of the patients, especially those whose cancer is resistant to platinum treatment.

ENMD-2076 is a novel small molecule kinase inhibitor with unique combination of mechanisms of action that involve inhibition of several pathways key to tumor growth and survival including angiogenesis, proliferation, and the cell cycle. Based on pre-clinical and Phase 1 clinical studies of ENMD-2076, we believed that the drug candidate may play a role in fitting some of the unmet medical needs. This Phase 2 trial further demonstrates the anti-cancer activity of ENMD-2076 in yet a difficult to treat patient population of platinum-resistant ovarian cancer with tolerable side effects.”

Notably, Dr. Matulonis also commented on the anti-cancer activity of ENMD-2076 in three ovarian clear cell carcinoma patients as follows:

ENMD-2076 also showed anti-cancer activities in patients with clear cell carcinoma [CCC], a histological subtype considered as chemo-resistant. Two of three [CCC] patients recruited had longer PFS than the median with one patient in stable disease for over two years. As recent reports suggest VEGF is frequently expressed in clear cell cancers, this subtype might be particularly responsive to therapies that incorporate VEGF inhibition. Further clinical evaluations of ENMD-2076 may therefore be warranted in this patient subset either as a single agent or in combinations.” [emphasis added]

Ken Ren, Ph.D., EntreMed’s Chief Executive Officer, further commented:

We are very pleased and honored to have this Phase 2 trial data published in such an esteemed journal. This is a further endorsement of the global medical and science community on the clinical and scientific value of ENMD-2076 in ovarian cancer treatment. We truly believe that ENMD-2076 may potentially offer unique and competitive advantages for unmet medical needs in such difficult to treat oncology indications including platinum-resistant and/or clear cell ovarian cancer in improving the patients’ quality and duration of life. We are committed to the global clinical development of ENMD-2076 for cancer patients who might benefit from its therapy. With the support of clinical investigators like Dr. Matulonis, their commitment and dedication, and the support from our long term shareholders, we are confident that we can achieve our goal.”

About EntreMed

EntreMed, Inc. is a clinical-stage pharmaceutical company employing a drug development strategy primarily in the United States and China to develop targeted therapeutics for the global market. Its lead compound, ENMD-2076, a selective angiogenic kinase inhibitor, has completed several Phase 1 studies in solid tumors, multiple myeloma, and leukemia, and is currently completing a multi-center Phase 2 study in ovarian cancer. EntreMed, Inc. recently initiated a dual-institutional Phase 2 study of ENMD-2076 in triple-negative breast cancer. Additional information about EntreMed is available on the Company’s web site at www.entremed.com.

About ENMD-2076

ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers. ENMD-2076 has shown promising activity in Phase 1 clinical trials in solid tumor cancers, leukemia, and multiple myeloma. ENMD-2076 is currently completing a Phase 2 trial for ovarian cancer. EntreMed, Inc. recently initiated a dual-institutional Phase 2 study of ENMD-2076 in triple-negative breast cancer.

ENMD-2076 received orphan drug designation from the United States Food and Drug Administration (FDA) for the treatment of ovarian cancer, multiple myeloma and acute myeloid leukemia (AML). In the United States, the Orphan Drug Act is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 people in this country. Orphan drug designation provides seven years of market exclusivity that begins once ENMD-2076 receives FDA marketing approval. It also provides certain financial incentives that can help support the development of ENMD-2076.

Citation:

Matulonis UA, Lee J, Lasonde B, et. al. ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer. Eur J Cancer. 2013 Jan;49(1):121-31.doi:10.1016/j.ejca.2012.07.020. PubMed PMID: 22921155.

Additional Source:

Dana-Farber Cancer Institute’s Ursula A. Matulonis, M.D. Article on EntreMed’s ENMD-2076 Published in the European Journal of Cancer, EntreMed, Inc. Press Release, Sept. 6, 2012.

ENMD-2076 Phase II Ovarian Cancer Clinical Trial Protocol Summary:

A Phase 2 Study of Oral ENMD-2076 Administered to Patients With Platinum Resistant Ovarian Cancer, ClinicalTrials.gov Identifier: NCT01104675 (study ongoing, but not recruiting patients).

Caris Life Sciences Launches Molecular Profiling Service For Ovarian Cancer Patients

Caris Life Sciences announces the launch of a new molecular profiling service for ovarian cancer patients

Caris Life Sciences, Inc. (Caris), a leading biosciences company focused on enabling precise and personalized healthcare through the highest quality anatomic pathology, molecular profiling, and blood-based diagnostic services, announced the launch of a new, Caris Target Now™ molecular profile for ovarian cancer patients. This expansion of the Caris Target Now™ offering provides individualized molecular information to treating physicians, relevant to the selection of therapies to treat this highly-lethal cancer. Ovarian cancer affects more than 20,000 women annually and produces some of the highest five-year mortality rates found among the 200+ types of cancer.

Caris Target Now™ molecular profiling examines the unique genetic and molecular make-up of each patient’s tumor so that treatment options may be matched to each patient individually.  Caris Target Now™ helps patients and their treating physicians create a cancer treatment plan based on the tumor tested. By comparing the tumor’s information with data from published clinical studies by thousands of the world’s leading cancer researchers, Caris can help determine which treatments are likely to be most effective and, just as important, which treatments are likely to be ineffective.

The Caris Target Now™ test is performed after a cancer diagnosis has been established and the patient has exhausted standard of care therapies or if questions in therapeutic management exist. Using tumor samples obtained from a biopsy, the tumor is examined to identify biomarkers that may have an influence on therapy. Using this information, Caris Target Now™ provides valuable information on the drugs that will be more likely to produce a positive response. Caris Target Now™ can be used with any solid cancer such as lung cancer, breast cancer, prostate cancer, and now, ovarian cancer.

Evidence Behind Caris Target Now™

Daniel D. Von Hoff, M.D., F.A.C.P., is the Executive Director of Caris Life Sciences' Clinical Research

A multi-center, prospective, pilot study first published in The Journal of Clinical Oncology (JCO) in October 2010 [1] — along with an accompanying editorial [2] —  determined that personalized cancer treatment tailored to a tumor’s unique genetic make-up identified therapies that increased progression free survival (PFS) over previous therapies in 27% of patients with advanced disease.

The purpose of the study was to compare PFS using a treatment regimen based on the molecular profiling (MP) of a patient’s tumor with the PFS determined for the most recent regimen on which the patient had experienced progression after taking that regimen for 6 weeks.  Unlike a typical control study, each patient was his or her own study control.  Tissue samples from patients with refractory metastatic cancer were submitted for MP in two formats including:

In many of these refractory tumors, targets for conventional therapies were identified, which was “a surprise finding,” according to Dr. Daniel Von Hoff, the Executive Director of Caris’ Clinical Research.  But the profiling also suggested therapies in cases where the treating physician was unsure regarding the next line of treatment. The MP approach was found to have clinical benefit for the individual patient who had a PFS ratio (PFS on MP selected therapy/PFS on prior therapy) of ≥ 1.3.  Among the 86 patient tumors that were profiled with Caris Target Now™:

  • 84 (98%) had a detected molecular target;
  • 66 of the 84 patients were treated with therapies that were linked to their MP results; and
  • 18 (27%) of 66 patients had a PFS ratio of ≥ 1.3 (95% CI, 17% to 38% range; one-sided, one-sample P = .007).

The study investigators concluded that it is possible to identify molecular targets in patients’ tumors. In 27% of the patients, the MP approach resulted in a longer PFS on a MP-based regimen than on the regimen that was based on physician’s choice.  “It was also encouraging to see that the overall survival in these 18 patients was better than that for the whole group of 66 patients (9.7 vs. 5 months),” said Von Hoff.

Of the 66 participants, 27% had breast cancer, 17% had colorectal cancer, and 8% had ovarian cancer; the remainder were classified as miscellaneous.  The improvement in PFS among the various types of cancer patients was as follows: 44% in patients with breast cancer, 36% in those with colorectal cancer, 20% in those with ovarian cancer, and 16% in the miscellaneous group.

The investigators in the study utilized Caris Target Now™ molecular profiling, which is currently available to oncologists and their patients.

“Oncologists commonly expect a 1-in-20 chance of patient response in 3rd- and 4th-line therapies.  This recent study suggests those odds can be improved to 1-in-4 when using therapeutic guidance provided by Caris Target Now™.”

Dr. Jeff Edenfield, a practicing oncologist with US Oncology, and routine user of Caris Target Now™

Since 2008, more than 15,000 cancer patients have received a Caris Target Now™ molecular profile. Caris Target Now™ has been designed to provide treating physicians with therapeutic options, often identifying anti-tumor agents that may not have been considered before. The Caris Target Now™ report is based on the genetic make-up of an individual patient’s tumor cross-referenced with a vast and growing proprietary database of clinical literature, correlating genetic tumor information to therapeutic response. Using biomarker-based therapies has been linked to the likelihood of a positive patient response.

James H. Doroshow, M.D., Director, Division of Cancer Treatment & Diagnosis, National Cancer Institute

In the accompanying JCO editorial, James H. Doroshow, M.D., the Director of the National Cancer Institute (NCI) Division of Cancer Treatment and Diagnosis, commented that the study by Von Hoff et. al. possessed several limitations. [2] The stated limitations of the study include (i) uncertainty surrounding the achievement of the study’s primary end point based upon use of the time-to-disease progression (TTP) index; (ii) limited prior experience with patients as their own controls, and (iii) lack of study randomization.  Despite these limitations, Dr. Doroshow noted that important lessons can be learned from the study conducted by Von Hoff et. al.

“First and foremost, this study vividly reminds us that the need for therapeutic intervention arises one patient at a time. When we sit with an individual who is trying to live with an advanced solid tumor after having already received several different chemotherapy regimens, it is unlikely that any published prognostic index or gene signature, as currently implemented, will be of much help in decision making—for physicians or for patients. [citation omitted]. Thus, a truly urgent need exists to move past the empiric therapeutic paradigm that launched the first half century of systemic oncologic treatment. [citation omitted]. Von Hoff et al have taken a noteworthy, albeit somewhat flawed, first step in this direction in their attempt to imagine a novel paradigm for cancer therapy, using the techniques of molecular tumor characterization on an individual patient basis. Future investigators of new cancer therapies should learn from this initial effort and focus on how these rapidly evolving molecular tools can be used in the development of an entirely new investigative model for the systemic treatment of cancer.”

Caris is currently conducting and initiating additional studies of Caris Target Now™ molecular tumor profiling through collaboration with leading institutions and cancer centers. 

With 300% growth in utilization in 2010, medical oncologists are recognizing the utility and value of this novel approach in providing improved care to patients. Physician adoption is rapidly accelerating, as Caris recently reached the threshold of providing Caris Target Now™ services to more than 1,000 patients per month. This new introduction for ovarian cancer is most relevant for physicians treating women who have progressed on platinum-based therapy and/or who need guidance for third-line treatment options. Caris Target Now™ for ovarian cancer offers the opportunity for these women to benefit from personalized and targeted therapy guidance based upon molecular profiling.

“Ovarian cancer is a highly-lethal cancer that presents distinct diagnostic and therapeutic challenges, often presenting no major symptoms until the cancer has metastasized,” said Dr. Les Paul, Caris’ Senior Vice President for Medical Affairs. “Choosing the optimal therapeutic intervention at the earliest possible stage is critical to extending progression free survival in ovarian cancer patients. With the introduction of the Caris Target Now™ ovarian profile, we are able to support physicians with as much information as possible, including the latest relevant clinical literature citations to aid them in making the best therapeutic decision possible for each patient.”

Examples of the potential use of an existing clinical trial drug to target a specific molecular characteristic possessed by an ovarian cancer include:

Use of Molecular Profiling By Leading Medical Institutions; Sponsorship By A Charitable Foundation

It should be noted that molecular profiling is already being used in clinical practice at several leading cancer institutions.  At Massachusetts General Hospital, (MGH), The MGH Cancer Centre uses a PCR-based mutation-detection assay and state-of-the-art robotic technology, called “SNaPshot,” to look for 130 known gene mutations in tumor tissue. “We are already using molecular profiling for all our lung cancer patients,” said Jeffrey Settleman, Ph.D., scientific director at the MGH Cancer Center, to Medscape Oncology in 2009. [12] “This has already had an impact on treatment decisions, and it appears to be improving treatment. We have seen better response rates and we hope that this will translate into better survival.”  In fact, MGH is engaged currently in the largest study aimed at matching tumor genomes to potential anticancer treatments. [13] It is our understanding that MGH performs molecular profiling currently on melanoma, leukemia, brain and metastatic breast cancer, and metastatic adenocarcinoma that start in the lung, colon or rectum.

Several other institutions are in the process of developing or have developed their own systems, including the University of Texas M.D. Anderson Cancer Center [14], and the Dana-Farber Cancer Institute [15].  All are striving to profile individual tumors so that therapy can be personalized, which means that it has a better chance of working because it targets specific mutations found in a patient’s tumor. The MP approach also prevents patients from being exposed to drugs that have a limited chance of success, eliminating toxicity and improving quality of life.

We should also note the Clearity Foundation sponsors molecular profiling services on behalf of ovarian cancer patients at no cost. The Clearity Foundation is a 501(c)(3) not-for-profit, founded by Laura Shawver, Ph.D., who is an ovarian cancer survivor and research scientist.  The Clearity Foundation seeks to improve treatment outcomes in recurrent and progressive ovarian cancer patients by providing diagnostic services that determine the molecular profile of the individual patient with the belief that a molecular “blueprint” is crucial to finding appropriate treatments.

About Caris Target Now™

Caris Target Now™ is a comprehensive tumor analysis coupled with an exhaustive clinical literature search, which matches appropriate therapies to patient-specific biomarker information to generate an evidence-based treatment approach. Caris Target Now™ testing provides information that may help when considering potential treatment options.

Caris Target Now™ begins with an immunohistochemistry (IHC) analysis. An IHC test measures the level of important proteins in cancer cells providing clues about which therapies are likely to have clinical benefit and then what additional tests should be run.

If there is access to a frozen sample of patient tissue available, Caris may also run a gene expression analysis by microarray. The microarray test looks for genes in the tumor that are associated with specific treatment options.

As deemed appropriate based on each patient, Caris will run additional tests. Fluorescent In-Situ Hybridization (FISH) is used to examine gene copy number variation (i.e., gene amplification) in the tumor. Polymerase Chain Reaction (PCR) or DNA sequencing is used to determine gene mutations in the tumor DNA.

Caris takes the results from each test and applies the published findings from thousands of the world’s leading cancer researchers. Based on this analysis, Caris Target Now™ identifies potential therapies for patients and their treating physicians to discuss.

Caris Target Now™ was developed and its performance characteristics were determined by Caris, a CLIA-certified medical laboratory in compliance with the U.S. Clinical Laboratory Amendment Act of 1988 and all relevant U.S. state regulations. It has not been approved by the United States Food and Drug Administration.

About Caris Life Sciences

Caris Life Sciences, a leading biosciences company, specializes in the development and commercialization of the highest quality anatomic pathology, molecular profiling, and blood-based diagnostic technologies, in the fields of oncology, dermatopathology, hematopathology, gastrointestinal pathology and urologic pathology. The company provides academic-caliber consultations for patients every day, through its industry-leading team of expert, subspecialty pathologists. Caris also offers advanced molecular analyses of patient samples through prognostic testing services and genomic, transcriptomic, and proteomic profiling to assist physicians in their treatment of cancer. Currently, Caris is developing the Carisome™ platform, a proprietary, blood-based technology for diagnosis, prognosis, and theranosis of cancer and other complex diseases. The company is headquartered in the Dallas metroplex, and operates laboratories at the headquarters, as well as in the Phoenix and Boston metro areas.

About Daniel Von Hoff, M.D., FACP, Executive Director, Caris Life Sciences Clinical Research

Daniel D. Von Hoff, M.D., is currently physician-in-chief and director of translational research at Translational Genomics Research Institute (TGen) in Phoenix, Arizona. He is also chief scientific officer for US Oncology and the Scottsdale Healthcare’s Clinical Research Institute.  He holds an appointment as clinical professor of medicine at the University of Arizona College of Medicine.

Dr. Von Hoff’s major interest is in the development of new anticancer agents, both in the clinic and in the laboratory. He and his colleagues were involved in the beginning of the development of many of the agents now in routine use, including: mitoxantrone, fludarabine, paclitaxel, docetaxel, gemcitabine, irinotecan, nelarabine, capecitabine, lapatinib and others.

At present, Von Hoff and his colleagues are concentrating on the development of molecularly targeted therapies particularly for patients with advanced pancreatic cancer. Dr. Von Hoff’s laboratory interests and contributions have been in the area of in vitro drug sensitivity testing to individualize treatment for the patient, mechanisms of gene amplification, particularly of extrachromosomal DNA, and understanding of and targeting telomere maintenance mechanisms. His laboratory work now concentrates on the discovery of new targets in pancreatic cancer.

Dr. Von Hoff has published more than 543 papers, 133 book chapters, and more than 956 abstracts. Dr. Von Hoff  also served on President Bush’s National Cancer Advisory Board from June 2004 through March 2010.

Dr. Von Hoff is the past president of the American Association for Cancer Research(AACR) (the world’s largest cancer research organization), a fellow of the American College of Physicians, and a member and past board member of the American Society of Clinical Oncology (ASCO). He is a founder of ILEX™ Oncology, Inc. (acquired by Genzyme after Ilex had 2 agents, alemtuzumab and clofarabine approved for patients with leukemia). He is founder and the editor emeritus of Investigational New Drugs – The Journal of New Anticancer Agents; and, editor-in-chief of Molecular Cancer Therapeutics. He is also proud to have been a mentor and teacher for multiple medical students, medical oncology fellows, graduate students, and post-doctoral fellows. He is a co-founder of the AACR/ASCO Methods in Clinical Cancer Research Workshop.

References:

1/ Von Hoff DD, Stephenson JJ Jr, Rosen P, et. al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010 Nov 20;28(33):4877-83. Epub 2010 Oct 4. PubMed PMID: 20921468.

2/ 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. Epub 2010 Oct 4. PMID: 20921466.

3/Addition of Dasatinib (Sprycel) to Standard Chemo Cocktail May Enhance Effect in Certain Ovarian Cancers, by Paul Cacciatore, Libby’s H*O*P*E*™, April 19, 2009.

4/UCLA Researchers Significantly Inhibit Growth of Ovarian Cancer Cell Lines With FDA-Approved Leukemia Drug Dasatinib (Sprycel®), by Paul Cacciatore, Libby’s H*O*P*E*™, November 11, 2009.

5/BMS-345541 + Dasatinib Resensitizes Carboplatin-Resistant, Recurrent Ovarian Cancer Cells, by Paul Cacciatore, Libby’s H*O*P*E*™, July 1, 2010.

6/PARP Inhibitor Olaparib Benefits Women With Inherited Ovarian Cancer Based Upon Platinum Drug Sensitivity, by Paul Cacciatore, Libby’s H*O*P*E*™, April 23, 2010.

7/ Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriersN Engl J Med. 2009 Jul 9;361(2):123-34. Epub 2009 Jun 24. PMID: 19553641.

8/Audeh MW, Penson RT, Friedlander M, et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol 2009;27(supplement):p. 15S.

9/PARP Inhibitor MK-4827 Shows Anti-Tumor Activity in First Human Clinical Study, by Paul Cacciatore, Libby’s H*O*P*E*™,  November 17, 2010.

10/PI3K Pathway: A Potential Ovarian Cancer Therapeutic Target?, by Paul Cacciatore, Libby’s H*O*P*E*™,  November 20, 2009.

11/Endocyte’s EC145 Produces Significant Anti-Tumor Activity In Advanced Stage Chemoresistant Ovarian Cancer Patients, by Paul Cacciatore, Libby’s H*O*P*E*™, October 21, 2009.

12/Massachusetts General Hospital Cancer Center To Genetically Profile All Patient Tumors, by Paul Cacciatore, Libby’s H*O*P*E*™, March 14, 2009.

13/Largest Study Matching Genomes To Potential Anticancer Treatments Releases Initial Results, by Paul Cacciatore, Libby’s H*O*P*E*™, August 3, 2010.

14/An Initiative for Molecular Profiling in Advanced Cancer Therapy (IMPACT) Trial. A Molecular Profile-Based Study in Patients With Advanced Cancer Treated in the Investigational Cancer Therapeutics Program, University of Texas M.D. Anderson Cancer Center, ClinicalTrials.gov Identifier: NCT00851032.

15/Dana-Farber Researchers “OncoMap” The Way To Personalized Treatment For Ovarian Cancer, by Paul Cacciatore, Libby’s H*O*P*E*™, November 16, 2010.

Sources:

Additional Information:

Girls with Stage I Ovarian Germ-Cell Tumors Can Safely Skip Chemotherapy Until Recurrence

Researchers from Dana-Farber/Children’s Hospital Cancer Center found that as many as 50 percent of young girls treated for germ-cell ovarian tumors may be safely spared chemotherapy using a “watch and wait” strategy to determine whether follow-up treatment is needed.

Researchers from Dana-Farber/Children’s Hospital Cancer Center (DF/CHCC) found that as many as 50 percent of young girls treated for germ-cell ovarian tumors may be safely spared chemotherapy using a “watch and wait” strategy to determine whether follow-up treatment is needed.

In contrast to the current practice of administering chemotherapy to all patients following removal of these rare tumors, researchers said the study demonstrated that treatment could safely be delayed and given only when the cancer recurred.

Data from the trial involving 25 young women ages 9 to 16 was presented at the 42nd Congress of the International Society of Paediatric Oncology (SIOP) in Boston on Friday, October. 22.

Lindsay Frazier, M.D., Pediatric Oncologist, Dana-Farber / Children's Hospital Cancer Center; Chair, Germ Cell Tumor Committee, Children's Oncology Group

The study was led by Lindsay Frazier, MD, a pediatric oncologist at DF/CHCC and chair of the Germ Cell Tumor Committee of the Children’s Oncology Group.

“I personally think that not giving chemotherapy to half the patients [women with germ cell ovarian tumors] is a good thing,” said Frazier. “The chemotherapy is just as effective given when the disease recurs. I would recommend that parents consider a watching and waiting strategy.”

Germ cell tumors are malignancies that develop in precursors of sperm cells in boys and egg cells in girls. Some forms of the tumors are most often detected immediately following birth; other types are most common between the ages of 10 and 30.

Previous trials had shown that delaying chemotherapy was safe and effective in Stage 1 germ cell testicular tumors in boys. Over time, 30 percent of the patients developed a recurrence, but they were all cured by chemotherapy.

“So instead of giving 100 percent of them chemotherapy, only 30 percent needed it,” explained Frazier, who said it’s been found that the usual three cycles of chemotherapy administered for the tumors doubles the long-term risk of cardiovascular disease or second cancers.

The current study was undertaken to test a similar watch-and-wait approach in female patients. Frazier said 25 girls with Stage 1 germ cell ovarian tumors were recruited from about 100 medical centers — an indication of the cancer’s rarity. In all cases, the tumors had been completely removed by surgery.

Instead of undergoing chemotherapy immediately, the girls were monitored closely for signs of recurrence. Every three weeks their blood was tested for biochemical markers signifying a regrowth of the cancer, and every three months they were scanned with CT or MRI imaging.

“The median time to relapse was two months, and the latest relapse was at 9 months, so the families were not living with uncertainty for a long time,” Frazier said.

The recurrence rate was 50 percent — higher than in the boys with germ cell tumors — but the delayed treatment was similarly effective though one girl died, yielding a survival rate of 96 percent.

Preventing unnecessary chemotherapy treatment for half of girls with such tumors is still desirable, said Frazier, “because there is evidence that girls are even more susceptible to long-term harm from chemo than boys are.”

The study was supported by the National Cancer Institute.

Sources:

2010-2011 U.S. News & World Report “Best Hospitals” List

This week, U.S. News & World Report issued its 2010-2011 rankings of the best U.S. hospitals for adults. The University of Texas, M.D. Anderson Cancer Center is rated #1 in cancer treatment, and Johns Hopkins is rated #1 in gynecology and #1 overall based upon all medical specialties.

If you would like more information regarding the 2010-2011 U.S. News & World Report best U.S. hospital rankings, click here. To better understand how U.S. News & World Report ranked the hospitals in each specialty, read Best Hospitals 2010-11: The Methodology, written by U.S. News & World Report’s Avery Comarow.  If you would like to review the current U.S. News & World Report America’s Best Children’s Hospitals list, click here.

Top 10 U.S. Hospitals: Cancer

Top 10 U.S. Hospitals: Gynecology

Top 10 U.S. Hospitals (highest scores in at least six medical specialties)
1. Univ. of Texas M.D. Anderson Cancer Center, Houston, Texas Johns Hopkins Hospital, Baltimore, Maryland Johns Hopkins Hospital, Baltimore, Maryland
2. Memorial Sloan-Kettering Cancer Center, New York, New York Mayo Clinic, Rochester, Minnesota Mayo Clinic, Rochester, Minnesota
3. Mayo Clinic, Rochester, Minnesota Brigham and Women’s Hospital,Boston, Massachusetts Massachusetts General Hospital, Boston, Massachusetts
4. Johns Hopkins Hospital, Baltimore, Maryland Cleveland Clinic, Cleveland, OH Cleveland Clinic, Cleveland, Ohio
5. University of Washington Medical Center, Seattle, Washington Massachusetts General Hospital, Boston, Massachusetts Ronald Reagan UCLA Medical Center, Los Angeles
6. Dana-Farber Cancer Institute, Boston, Massachusetts Magee-Womens Hospital of Univ. of Pittsburgh Medical Center, Pittsburgh, Pennsylvania New York-Presbyterian Univ. Hospital of Columbia & Cornell, New York, New York
7. Massachusetts General Hospital, Boston, Massachusetts Duke University Medical Center, Durham, North Carolina Univ. of California, San Francisco (UCSF) Medical Center
8. Univ. of California, San Francisco (UCSF) Medical Center Univ. of California, San Francisco (UCSF) Medical Center Barnes-Jewish Hospital/Washington University, St. Louis
9. Cleveland Clinic, Cleveland, Ohio New York-Presbyterian Univ. Hospital of Columbia & Cornell, New York, New York Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
10. Ronald Reagan UCLA Medical Center, Los Angeles Memorial Sloan-Kettering Cancer Center, New York, New York Duke University Medical Center, Durham, North Carolina