Research Discovery May Offer New Treatment Options for People Diagnosed With Rare Form of Ovarian Cancer

A recent finding by researchers at UBC’s faculty of medicine and the BC Cancer Research Institute (BCCRI) may offer a new treatment possibility for people diagnosed with a rare and aggressive form of ovarian cancer.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a devastating cancer that has no effective treatments and is usually diagnosed in women in their 20s. The study, published in Clinical Cancer Research, describes a metabolic vulnerability present in cells that may represent a therapeutic target if proven in clinical trials.

“Finding this vulnerability and identifying a way to exploit it could have a huge impact for anyone diagnosed with this rare disease,” said the study’s first author Jennifer Ji, an MD/PhD candidate at UBC’s faculty of medicine and BCCRI trainee.

The discovery is welcome news to Justin Mattioli, whose 34-year-old wife Eileen passed away from SCCOHT in the spring of 2019. Prior to her passing, Eileen made the decision to donate her tissue samples to help advance cancer research in the hopes of finding new treatments for others facing the disease.

“We would hate to see someone else go through what Eileen did,” said Justin. “And there is a good possibility that this may help advance further research into other types of cancers as well.”

Eileen’s samples are being used as a new cell model, enabling researchers to test the effects of new treatments and to better understand the biology of the disease.

The team found that SCCOHT cancer cells have very low levels of an enzyme necessary for the production of arginine, an amino acid needed to help our cells build protein.

Non-cancerous cells have this enzyme and can produce their own arginine, but tumours without it cannot produce this amino acid themselves, meaning they need to be in an arginine-rich environment to survive.

Dr. David Huntsman

Using a small molecule agent, the team has found a way to eliminate arginine in the tumour environment, essentially starving the cancer to death while having minimal effect on normal cells.

“This agent basically absorbs all of the arginine within the tumour environment so cells can’t produce it themselves, thus starving the tumor,” said research team lead Dr. David Huntsman, a professor in the departments of pathology and laboratory medicine and obstetrics and gynaecology at UBC and a pathologist and ovarian cancer researcher at BC Cancer. “As such vulnerability has been also discovered in several other cancer types, we are now looking to partner with other research organizations who are evaluating these treatment options in patients whose cancer lacks the expression of this particular enzyme.”

So far, researchers have validated this treatment in pre-clinical studies. They are now exploring combination therapy, with the use of Eileen’s samples, in an effort to boost the response and avoid potential resistance. In addition, they want to test their findings in clinical trials.

“This research is another step to better understanding a very aggressive form of ovarian cancer and providing better treatment outcomes for women diagnosed with this disease,” said Huntsman.

The study was funded by the Terry Fox Research Institute, the BC Cancer Foundation, the VGH & UBC Hospital Foundation and a number of other funding partners.

This article was published by UBC Faculty of Medicine.

HIPEC With Cytoreductive Surgery Effective in Ovarian Cancer

By Sarah Williams

For patients with stage III epithelial ovarian cancer, adding hyperthermic intraperitoneal chemotherapy (HIPEC) to primary cytoreductive surgery (PCS) increases survival compared with PCS alone, according to results of a retrospective study now published in JAMA Network Open.

Of all the gynecologic cancers, ovarian cancer is the most deadly. This may be due in part to the fact that in almost 70% of cases, by the time a patient is first diagnosed with ovarian cancer, it has already spread beyond the ovaries into the peritoneal cavity.

The standard treatment for surgical candidates involves optimal PCS with platinum/paclitaxel-based intravenous chemotherapy; however, “nearly 70% of patients with advanced ovarian cancer relapse and die of the disease, even after standard-of-care treatment according to clinical guidelines,” write the study investigators, led by first author Ziying Lei, MD, of the Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China. “Given that the peritoneal cavity is the primary site of tumor invasion and can be continuously exposed to a high concentration of chemotherapeutic agents, it seems rational to administer intraperitoneal chemotherapy directly into the peritoneum.”

Yet intraperitoneal chemotherapy administration poses some difficulties, in that many patients develop complications related to the catheter. More tolerable methods of therapeutic delivery are needed.

One possible solution is HIPEC, in which intraperitoneal delivery of chemotherapy is combined with hyperthermia. The use of HIPEC is more tolerable for patients and avoids the catheter-related issues; in addition, it increases the accumulation of the drug in the cancer cells and seems to amplify the chemotherapy’s cytotoxic effects. There is high-quality evidence in favor of HIPEC use in advanced ovarian cancer, and it is in widespread use; however, no modern multicenter, large-scale studies have examined the impact on prognosis of combining PCS with HIPEC in epithelial ovarian cancer until now.

For this retrospective cohort study, 584 patients with stage III primary epithelial ovarian cancer at five large institutions in China were treated with either PCS alone (425 patients, or 72.8% of the study population) or PCS with HIPEC (159 patients, or 27.2%). Patients were followed for a median of 42.2 months.

Treatment was well tolerated in both groups. Following adjustment using the inverse probability of treatment weighting (IPTW) method, PCS with HIPEC resulted in an increased median survival time compared with PCS alone (49.8 vs 34.0 months) and an increased three-year overall survival rate (60.3% vs 49.5%). Among patients who underwent complete surgical procedures, PCS with HIPEC increased both median survival time (53.9 vs 42.3 months) and three-year overall survival rate (65.9% vs 55.4%). For patients who underwent incomplete surgical procedures, adding HIPEC to PCS increased median survival time (29.2 vs 19.9 months) but did not produce a statistically significant difference in three-year overall survival rate (44.3% vs 36.7%, P=0.19).

“In this study, the PCS with HIPEC treatment approach was associated with better long-term survival and was not associated with postoperative severe morbidity and mortality,” conclude Dr. Lei and colleagues. “When complete PCS is possible, this approach can be a valuable therapy among patients with stage III epithelial ovarian cancer.”

In an invited commentary published alongside the study in JAMA Network Open, led by first author Raanan Alter, MD, of the Department of Obstetrics and Gynecology’s Section of Gynecologic Oncology at the University of Chicago, the authors note several limitations of the study, including the potential for selection bias present in a retrospective study, the imbalance between the two cohorts, and the fact that more patients given PCS with HIPEC underwent at least 6 chemotherapy cycles compared with the PCS-only group (51.8% vs 35.2%). The authors also note that the patients represent a heterogenous group, that the unusual method of multiday HIPEC with lower-dose cisplatin (50 mg/m²) used in the study is not based on strong phase 1 trial data, and that the study lacked consideration of tumor genomic data, surgical outcomes, and recurrence patterns.

“Nevertheless, the study by Lei et al adds to recent evidence indicating that the addition of intraperitoneal chemotherapy with HIPEC, whether upfront or at interval debulking, might improve overall survival,” conclude Dr. Alter and colleagues. “It would appear to us, after reviewing the available published evidence supporting the use of HIPEC, that one should discuss the use of HIPEC preoperatively with patients with stage III, low-volume disease who are thought to likely experience optimal (R0) cytoreduction. From the data presented by Lei et al, one could argue that even patients with large volumes of residual disease could benefit from HIPEC with PCS, but the data are less convincing and need further investigation.”

“We expect that remaining questions will be conclusively answered by a phase 3 randomized trial that just opened this year,” write Dr. Alter and colleagues, referring to the international OVHIPEC-2 trial (NCT03772028), results of which are not expected to be available until 2026. “Until then, we expect that more institutions will publish their experiences with HIPEC to help guide decision-making on its use in the upfront treatment of ovarian cancer.”

This article was published by i3 Health Oncology News.

STING Activation Touted as Potential Immunotherapy for Cancer

A Scripps Research team reports the discovery of a molecule that can activate a natural immune-boosting protein called STING. The findings mark a key advance in the field of oncology, as the STING protein is known for its strong antitumor properties, according to the scientists.

STING (short for STimulator of INterferon Genes) marshals the immune system against viral and cancerous invaders and, because of its role in promoting antitumor immunity, has garnered much interest from drug developers.

However, STING’s natural activators in the body are unstable DNA-related molecules that do not last long in the bloodstream. That has hindered the development of treatments based on them, and has prompted a search for a hardier STING-activating small molecule, i.e., one that can circulate in the blood and work against tumors systemically, wherever they may exist in the body.

The researchers, who published their finding “Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic” in Science, screened a set of suitable small molecules with diverse structures and identified several that activate STING. After modifying one of these molecules to optimize its properties, they found that delivering it systemically into mice with an injection greatly reduced the growth of an aggressive form of melanoma.

“Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands,” write the investigators.

“From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity.”

“A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) mimetic that induces the same ‘closed’ conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming.”

“SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.”

The discovery raises the possibility of a circulating drug that could activate STING and suppress a wide range of cancers.

“A systemic STING-activating molecule could have considerable utility, and not only as a therapeutic for cancer and infectious disease, but also as a probe for studying STING-dependent antitumor immunity and a host of other STING-related biological processes,” says co-senior author Luke Lairson, PhD, an associate professor in the department of chemistry at Scripps Research.

Lairson and colleagues found that their optimized STING-activator, which they named SR-717, appears to activate the STING protein in the same way as its natural activators in the body. Using X-ray crystallography to image the interaction at atomic scale, they showed that both SR-717 and a known natural activator bind to the same site on STING and induce the same shape-change in the protein.

In an animal model of aggressive melanoma, SR-717 dramatically suppressed tumor growth, prevented metastasis, induced the presentation of tumor molecules to the immune system, and robustly boosted levels around tumors of CD8+ T cells and NK cells–both of which are known to be among the immune system’s heaviest antitumor weapons. At this effective dose, there was no evidence of significant adverse side effects on the animals.

Lairson and colleagues are continuing to study SR-717, with the hope of developing it into a new anticancer treatment that could be used alone or in combination with other treatments.

This article was published by ClinicalOMICS. 

Tumor Gene Test Could Help to Predict Ovarian Cancer Prognosis

A global team of medical researchers led by UNSW have developed a test that could help to predict survival for women diagnosed with ovarian cancer, and pave the way towards personalised treatment.

A tumour test could help to identify ovarian cancer patients with predicted poor survival, and down the track inform new therapeutical approaches, the results of a major international collaboration have shown.

The research paper led by UNSW Medicine — involving 125 authors across 86 organisations, including University of Southern California (USC), University of Cambridge, University of British Columbia, Huntsman Cancer Institute, Mayo Clinic, and Peter MacCallum Cancer Center in Melbourne — was published in Annals of Oncology.

In 2020, it is predicted that 1,532 Australian women will be diagnosed with ovarian cancer, and 1,068 will die from the disease this year. It has poor survival and the type studied in this paper — high grade serous ovarian cancer — is the most common and worst survival type. Ovarian cancer is the eighth most commonly occurring cancer in women, with nearly 300,000 global new cases in 2018.

“We conducted an analysis of 3,769 tumour samples from women with ovarian cancer and found we were able to reliably use a piece of tumour to determine how good a woman’s survival chances would be five years after diagnosis,” says lead author Professor Susan Ramus from UNSW Medicine.

The researchers found their gene expression test was substantively better at predicting survival than using a patient’s age and cancer stage.

“When women were divided into five groups, we found that the women whose tumour gene expression was associated with the best prognosis had nine years survival, whereas the women in the poorest survival group have two years survival, which is a very big difference,” Professor Ramus says.

“Our vision is that clinicians could use our test at diagnosis to identify the group of patients who wouldn’t do well on the current treatments and potentially offer them alternatives — for example, we may be able to put those patients into clinical trials and offer them different treatments that may improve their survival.”

For the study, the team used a training set of samples and a test set — nearly 4000 samples in total.

“Using novel statistical approaches, we analysed data from six previous gene expression studies, which helped us identify genes likely to be involved in high grade serous ovarian cancer survival,” says the paper’s first author, Dr Joshua Millstein from USC.

After putting together a panel of about 500 candidate genes, the team measured gene expression in the 4000 samples using the NanoString platform.

“To predict survival from gene expression, we chose one of four machine learning methods, an approach called ‘elastic net’, which performed the best in the training data,” Dr Millstein says.

“We used the training set to determine what genes could be used in the prediction, and then we tested them to see whether we got the same results in the other set,” Professor Ramus says.

Professor Ramus is the co-founder of the Ovarian Tumour Tissue Analysis (OTTA) consortium, an international group of researchers that are working on a number of different large-scale projects, using the samples compiled by the consortium to address important clinical questions.

“The consortium is unique in this space because it has access to thousands of samples — which is a lot of samples for a rare disease like ovarian cancer,” she says.

“That’s what enabled us to develop this prognostic tool — other groups have tried before to look at prognosis, but nothing has been used clinically. At the moment, only patient age and stage are used to determine survival, so something like our tool is sorely needed.”

The researchers say they selected genes for analysis that had known drug targets.

“Some of the genes we identified as being predictors for good or poor survival may be potential targets for new treatments. At the moment the majority of ovarian cancer patients get the same treatment — it’s not like breast cancer or other cancers where they look at your tumour and select from a range of treatments. So this is a way to stratify patients and potentially give more personalized treatment down the track.”

To validate the findings further, the research team wants to include the test in a prospective study and clinical trials.

“Potentially, we could incorporate it within a clinical trial so that the women who are predicted to have poor survival could get alternative treatments as rapidly as possible,” Prof. Ramus says.

The researchers hope their test will be ready for clinical use in the near future.

This article was published by Science Daily.

Local Resident Oversees Potential COVID-19 Pneumonia Treatment

By Luke Harold

As chairman and CEO of CalciMedica, Rachel Leheny is overseeing the development of a potential treatment for organ damage caused by COVID-19 pneumonia.

“Our lead compound Auxora is in clinical development in COVID-19 pneumonia,” said Leheny, who recently moved to La Jolla from Rancho Santa Fe. “And we also have data from a pancreatitis study that we’ve done. The drug is targeted at acute inflammatory diseases, and we’re going to be moving into a blinded, sort of registration study for COVID-19 pneumonia.”

In April, the FDA granted permission for the company to proceed with its study on Auxora for patients with severe COVID-19 pneumonia who are at risk for progression to acute respiratory distress syndrome

“The FDA’s quick decision to allow CalciMedica to proceed with dosing of COVID-19 patients underscores the potential of CM4620-IE (later named Aurora) to benefit these patients,” Sudarsha Hebber, CalciMedica’s chief medical officer, said in a statement in April.

The statement continued, “Patient safety is key for us as we rapidly evaluate CM4620-IE in patients with severe COVID-19 pneumonia. Due to the fast-acting nature of the drug, it may quickly lessen the cytokine storm associated with COVID-19 and may stabilize the pulmonary endothelial capillary barrier and prevent more serious lung injury.”

Charles A. Bruen, a critical care and emergency physician at Regions Hospital in Minnesota, where a Phase 2 clinical study was set to take place, added in a statement that “there is a dire need for a fast-acting, potent treatment for patients with severe COVID-19 pneumonia.”

Leheny, who has lived in North County for about 17 years, has been CEO of CalciMedica since December.

“I’ve been in biotech in one form or another for 25 years,” she said.

Leheny received her bachelor’s degree in chemistry from Harvard, followed by a Ph.D. in chemistry from Columbia and postdoctoral research in chemistry at UC Berkeley.

Previous posts she’s held include head of biotechnology research at the now defunct financial firm Lehman Brothers, as well as founder and managing director of Caxton Advantage Life Sciences, a life science venture capital firm.

Leheny is also a founder of the Clearity Foundation, which provides support for women who have ovarian cancer. Through its newest program, Steps Through OC, patients receive six months of personalized psychosocial counseling from certified ovarian cancer counselors.

“You’re trying to help people dealing with very critical illnesses,” Leheny said of the commonality between her work with CalciMedica and the Clearity Foundation.

For more information, visit calcimedica.com and www.clearityfoundation.org.

This article was published by Del Mar Times.

Study Finds Patients With Rare Ovarian Cancer Develop Chemoresistance

Patients with LGSC also had a significantly lower partial response rate with neoadjuvant therapy compared with patients with HGSC.

By Christina Bennett, MS

Patients with low-grade serous carcinoma of the ovary or peritoneum (LGSC) developed chemoresistance to neoadjuvant platinum-based therapy, reported a single-institution study in Gynecologic Oncology.

Using a longitudinal database, study researchers identified 36 patients with LGSC who received neoadjuvant therapy between 2003 and 2018 at MD Anderson Cancer Center. Houston, Texas. Patients were matched to a convenience sample of 36 patients with high-grade serous carcinoma of the ovary or peritoneum (HGSC) who received neoadjuvant therapy and were identified using an institutional database.

All patients were treated with neoadjuvant platinum-based chemotherapy and received a similar median number of cycles: 5 cycles for LGSC (range, 3-9 cycles) and 4 for HGSC (range, 3-9 cycles).

Although a similar proportion of patients with LGSC and HGSC underwent interval cytoreductive surgery (81% vs 89%, respectively), complete cytoreduction was achieved in a significantly lower proportion of patients with LGSC compared with HGSC (38% vs 75%, respectively; P =.002). Patients with LGSC also had a significantly lower partial response rate with neoadjuvant therapy compared with patients with HGSC (11% vs 75%, respectively); no complete responses were seen.

Patients with LGSC did achieve a 52% decrease in CA-125 levels after treatment, which was statistically significant (P <.001), but the drop was less pronounced than the 96% decrease seen among patients with HGSC (P <.001).

“This study provides further evidence of relative chemoresistance of LGSC in patients treated with [neoadjuvant therapy] NACT,” the study authors concluded.

Previously the study authors showed that among 24 patients with LGSC treated with neoadjuvant chemotherapy, only 1 patient (4%) achieved a response, which was a complete response.

“This does not suggest that we should abandon neoadjuvant treatment altogether,” the study authors cautioned. “Instead, this is further evidence that we are in serious need of novel therapies for LGSC patients that extend beyond traditional platinum-based chemotherapy.”

This article was published by Cancer Therapy Advisor.