Can PARP Inhibitors and Immune Checkpoint Inhibitors Improve Outcomes in Ovarian Cancer?

By Dave Levitan

The combination of a poly (ADP-ribose) polymerase (PARP) inhibitor and immune checkpoint inhibition with tislelizumab was well tolerated and showed promising anti-tumor activity in a phase I trial of patients with multiple solid tumor types, according to a new study published in Lancet Oncology. Ovarian cancer was the most commonly represented tumor type in the trial.

“Non-clinical data have demonstrated a direct association between DNA damage and immune responses, which supports the combined use of checkpoint inhibitors and PARP inhibitors,” wrote study authors led by Michael Friedlander, MBChB, PhD, of the Nelune Comprehensive Cancer Centre at Prince of Wales Hospital in Sydney, Australia. “Tumors that respond to PARP inhibition might have an enhanced sensitivity to combined treatment with a PARP inhibitor and an anti-PD-1 antibody, and the efficacy and safety of the two drugs administered together deserves further investigation.”

The new phase 1a/b study included a total of 49 patients with solid tumors, including 34 with ovarian, fallopian tube, or primary peritoneal cancer. They were treated with a combination of the PARP 1/2 inhibitor pamiparib and the anti-PD-1 monoclonal antibody tislelizumab in several dose escalation cohorts.

The full cohort had a median age of 63 years, and 86% of patients were women. No tumor type other than ovarian cancer was represented in more than three patients; other tumor types included pancreatic, prostate, breast, bile duct, and others.

In total, 20% of patients achieved an objective response to the therapy; two patients (4%) achieved a complete response, and eight patients (16%) achieved a partial response. Both of the patients with a complete response had BRCA-wildtype ovarian tumors. Seven of the 8 patients with a partial response had ovarian, fallopian tube, or peritoneal cancer, while the other patient had breast cancer.

Another 16 patients (32%) had stable disease as their best response, for a disease control rate of 53%. Sixteen of the 34 ovarian cancer patients had a response or stable disease.

The most common treatment-emergent adverse events with the pamiparib-tislelizumab combination were nausea (63% of patients), fatigue (53%), diarrhea (35%), and vomiting (31%).

Four patients experienced a dose-limiting toxicity, including grade 2 nausea, grade 3 rash, grade 2 nausea and vomiting, and grade 4 immune-related hepatitis. The recommended phase II dose was determined to be tislelizumab 200 mg every 3 weeks plus pamiparib 40 mg twice daily.

“The combination of pamiparib and tislelizumab exploits the potential accumulation of DNA damage resulting from PARP inhibition, which in turn might increase infiltration of immune cells into the tumor microenvironment, thereby increasing cancer cell killing,” the authors wrote. “Overall, the data presented support the continued investigation of pamiparib and tislelizumab, with close monitoring of liver function tests, in tumor-specific cohorts who are most likely to benefit from this combination therapy.”

In an accompanying editorial, Ulrik Lassen, MD, PhD, of Rigshospitalet in Copenhagen, noted that at least nine other trials are currently exploring the possibility of combining PARP inhibition with immune checkpoint inhibition, and he agrees that there is “strong rationale” for exploring these combinations.

“It is very encouraging that the safety and pharmacokinetic profiles of the combination in general were similar to the profiles of each drug when given as monotherapy and similar to other PARP inhibitors and checkpoint inhibitors,” Lassen wrote.

This article was published by Cancer Network.

Researchers Develop Early Detection Test for Ovarian Cancer

Researchers from Queen’s University Belfast have developed a test that may be able to detect ovarian cancer up to two years earlier than current approaches.

The researchers discovered that the presence of four proteins together, known as a biomarker panel, indicates the likelihood of Epithelial Ovarian Cancer (EOC), a type of ovarian cancer. Using these biomarkers the researchers then developed a screening test that initial studies suggest may be able to detect ovarian cancer up to two years before current detection tests.

The research was carried out in partnership with the University of New South Wales Australia, University of Milan, University of Manchester and University College London.

The study, published in British Journal of Cancer, involved the analysis of blood samples from 80 individuals across a seven-year period.

Dr. Bobby Graham from the School of Biological Sciences at Queen’s University Belfast and lead author of the study explains: “Firstly, we discovered that the presence of the biomarker panel will enable us to detect EOC. We then developed a screening test to detect this biomarker panel, making this a relatively simple diagnostic test.

“The algorithm designed will screen the blood sample and flag any abnormal levels of the proteins associated with the cancer. The screening test identifies ovarian cancer up to two years before the current tests allow.”

Most ovarian cancers are epithelial ovarian cancers, which is a cancer that forms in the tissue covering the ovary.

In females in the UK, ovarian cancer is the sixth most common cancer. In 2016, 4227 deaths were reported as a result of EOC.

If diagnosed at stage one of EOC, there is a 90 percent chance of five-year survival compared to 22 percent if diagnosed at a stage three or four.

Dr. Graham added: “The results of this study are encouraging, however, we now want to focus on testing it in a wider sample set so that we can use the data to advocate for an ovarian cancer screening programme.”

Dr. Rachel Shaw, Research Information Manager at Cancer Research UK, said: “Around half of ovarian cancer cases are picked up at a late stage, when treatment is less likely to be successful. So developing simple tests like these that could help detect the disease sooner is essential.

“At Cancer Research UK, we’re working hard to find new ways to detect cancer early and improve the tests already available. It’s really exciting to see these encouraging results for this type of ovarian cancer.”

This article was published by Medical Xpress.

AstraZeneca’s Ovarian Cancer Drug Hits Main Goal in New Study

By John Lauerman

AstraZeneca Plc’s Lynparza got a boost from results of a study that may widen the drug’s use among patients with advanced ovarian cancer.

Ovarian tumor growth slowed in patients who got Lynparza in addition to a standard treatment compared with those who got a placebo along with the treatment, according to a statement from Cambridge, U.K.-based Astra and Merck & Co., its U.S.-based partner in developing the drug.

Astra gained as much as 1.8% in early London trading.

Lynparza is approved to treat ovarian tumors that have mutations in a gene called BRCA that makes them more vulnerable to the therapy. The study, called Paola, treated patients with and without the mutations, showing a much broader level of utility.

The drug, called a PARP inhibitor, attacks tumors by thwarting the repair mechanisms of cells with gene flaws, rendering them unable to grow. The Paola study was spurred by the theory that many patients on standard ovarian cancer therapy develop flaws in repair, raising that possibility that Lynparza might help them.

Astra has been looking to the study to persuade doctors to use Lynparza more frequently. Analysts estimate about $2.6 billion in 2023 sales of the drug; a positive outcome from Paola would add to those projections, according to Sam Fazeli, a Bloomberg Intelligence analyst.

Astra expects to apply for an expanded label based on the study by the end of the year.

Other PARP inhibitors include GlaxoSmithKline Plc’s Zejula and Clovis Oncology Inc.’s Rubraca.

Ovarian cancer has few good treatments. Four out of five patients are diagnosed with advanced disease that has begun spreading. Less than a third of women live five years after diagnosis with metastatic ovarian cancer.

Other recent studies have indicated that Lynparza can treat certain forms of pancreatic and prostate tumors. Astra has an agreement with Merck to co-develop and commercialize the drug.

This article was published by Bloomberg.

Ovarian Cancer: Is this the Beginning of the End?

By Michael J. Birrer, MD, PhD

There will be 22,530 new cases of ovarian cancer in the United States this year.

Although tumors often present at an advanced stage, it remains one of the most chemosensitive epithelial cancers, with a response rate of 70% to 80% after initial surgery and chemotherapy.

Unfortunately, most patients relapse and develop chemotherapy-resistant disease. Approximately 14,000 U.S. women will die this year of ovarian cancer. No gynecologic malignancy has a higher fatality rate.

Despite decades of research into the pathogenesis and molecular origins of ovarian cancer, progress has been quite slow. Carboplatin and paclitaxel have been the standard therapy for more than 15 years.

However, in the last decade, there has been a revolution in our understanding of the origin of this tumor and its important molecular pathways. This has led to the development of novel effective therapies and, ultimately, better clinical management of the disease.

These advances have generated optimism that we may begin to see more women cured of this disease, or effectively managed so they can live long, comfortable lives.

The major new discoveries that contributed to this optimism include the recognition of the fallopian tube as a source for many ovarian cancers; large-scale systematic molecular analysis of high-grade serous ovarian cancers; and the development, testing and FDA approval of new agents, such as bevacizumab (Avastin, Genentech) and poly (ADP-ribose) polymerase (PARP) inhibitors.

Ovarian cancer is not ovarian cancer

One of the conundrums in ovarian cancer research for many years was the lack of validated preneoplastic lesions for this tumor.

The discovery and understanding of BRCA1/BRCA2 mutations as the basis of breast-ovary syndrome established a group of high-risk women.

Prophylactic removal of these patients’ ovaries and tubes allowed for the first time a systematic examination of pathologic specimens from high-risk patients. Even then, the identification of preneoplastic lesions on the ovarian surface was difficult to establish.

When several laboratories and pathologists began to examine the fallopian tubes, it became clear these patients harbored preneoplastic lesions in the surface epithelium of the fallopian tubes, with most located toward the distal end near the fimbria.

These lesions — called serous tubal intraepithelial carcinomas — have been found in a significant number of prophylactically removed specimens, and there is a general consensus that these are preneoplastic lesions for high-grade serous tumors.

Other abnormalities in the tubes, such as p53 signatures — clonal expansions of normal-appearing epithelial cells that stain for TP53 — remain to be defined. However, this work radically changed ovarian cancer research.

It provided a source of new, important tissue, which can be used to examine the early events in tumor development, along with potential genomic and protein markers that may be valuable for early detection. Further, it raised the issue of removing the fallopian tube alone as opposed to the ovary as a risk-reducing procedure.

Molecular analysis

The work of many laboratories over the past 10 years has provided a molecular underpinning for the observation that ovarian tumors of different histologies have unique clinical and anatomic differences.

Molecular analysis demonstrated that high-grade serous ovarian cancers are the result of genomic chaos with a major defect in DNA repair; clear cell cancers result at least, in part, from inactivation of ARID1A, a gene involved in chromatin structure; mucinous tumors of the ovary behave much like their gastrointestinal counterparts and likely are the result of aberrant RAS/RAF signaling; and endometrioid cancers behave like their endometrial counterparts with abnormalities in the PI3K pathway.

These molecular differences reinforced that these tumors are unique diseases and require separate clinical investigation.

The Cancer Genome Atlas study examined the genomic features of high-grade serous ovarian cancer on multiple platforms. Although the results reinforced many of the previously known genomic aspects of this tumor, this study provided a launching point for many new hypotheses and potential treatment algorithms.

A high-grade ovarian serous cancer results from a severe defect in DNA repair. This results, at least in part, from mutations in p53 and in BRCA1/BRCA2 or one of the other genes within the Fanconi DNA repair pathway. This produces a homologous recombination deficiency that creates an inability to repair DNA double-stranded breaks.

As a result of this abnormality, the tumor has very few high-frequency mutational events outside of p53 or BRCA1/BRCA2. This tumor cannot be targeted effectively by small molecule inhibitors.

The abnormality in homologous recombination deficiency results instead in the shift of large amounts of DNA, producing amplifications in the lesions throughout the genome. The precise genes that drive the tumor remain to be defined, and that is one of the challenges in the molecular characterization of ovarian cancer.

In addition, the genomic plasticity of high-grade serous ovarian cancer has raised issues of the degree of heterogeneity that exists within tumor diagnosis and its evolution under the pressure of therapeutic intervention.

New therapies

After little progress in the development of new ovarian cancer therapies in the 1990s and early 2000s, a better understanding of the activated molecular pathways led to 10 new indications in the past 5 years.

Early work on the microenvironment of ovarian cancer tumors suggested this tumor was, in part, a VEGF-driven tumor.

In early drug development trials, bevacizumab demonstrated an acceptable response rate and very high 6-month PFS rate among patients with platinum-resistant disease.

This was translated into an upfront randomized phase 3 trial known as GOG-0218 and its European counterpart, ICON7. Both studies demonstrated a statistically significant PFS benefit for patients who had been treated with bevacizumab concurrently with chemotherapy and in maintenance.

This led to the approval of the drug in Europe, but unfortunately, because there was no OS difference, it was not approved in the United States. It took several more years and a European study called AURELIA, which was focused on platinum-resistant patients. AURELIA looked at bevacizumab in combination with physician’s choice chemotherapy compared with chemotherapy alone. In the setting of recurrent platinum-resistant disease, results showed a statistically significant prolongation of PFS of approximately 3.5 months and an improvement in quality of life in these patients. This trial led to the approval of bevacizumab for ovarian cancer in the United States.

That was rapidly followed by additional studies, including OCEANS and GOG-0213, all of which focused on the use of bevacizumab in platinum-sensitive recurrence. These trials also showed a prolongation of PFS in favor of bevacizumab of approximately 4 to 5 months and led to FDA approval. Finally, just recently, with the summation of all data, the FDA approved the use of the drug upfront for patients with ovarian cancer.

The use of bevacizumab for ovarian cancer is well-established. It is used primarily for recurrent disease but, with time, may migrate toward upfront treatment.

The discovery and characterization of high-grade serous ovarian cancer as a disease of genomic instability prompted scientists to question whether it is targetable.

Early work began to focus on the PARP protein as being heavily involved in the repair of single-stranded breaks. Inhibition of single-stranded breaks will lead to double-stranded breaks, which cannot be repaired unless homologous recombination is intact. It was a wonderful example of bench-to-bedside efforts that led individuals to hypothesize that inhibition of the PARP protein should be particularly effective for tumors with BRCA1 or BRCA2 mutations.

The early laboratory data supported this hypothesis of synthetic lethality with a number of seminal publications in high-impact journals. This led to a relatively rapid translation of this concept into early drug development and, ultimately, to randomized phase 3 trials.

These trials have been an astonishing leap forward in that the laboratory-observed synthetic lethality could be demonstrated in patients, with an HR in favor of PARP inhibition in these trials frequently in the 0.2 to 0.3 range.

The initial approvals for this class of drugs in the United States were based on treatment and response rates.

Subsequent randomized, double-blind, placebo-controlled trials evaluated PARP inhibitor maintenance therapy for patients with high-grade serous ovarian cancer that had responded to a platinum regimen.

Three trials that evaluated women with platinum-sensitive recurrent disease — NOVA, SOLO2 and ARIEL3 — were strongly in favor of PARP inhibition. Of note, the NOVA trial treated all comers, and even those patients who had wild-type BRCA1/BRCA2 and scored normal in homologous recombination deficiency assays benefited from PARP inhibition.

The results of the SOLO-1 trial demonstrated that, for patients with germline or somatic BRCA1 or BRCA2mutations, maintenance in the frontline is very effective. Use of PARP inhibitors in ovarian cancer has now moved up to maintenance in frontline therapy.

These agents have been extremely well-tolerated, with some class effects of nausea and fatigue that usually are reasonably well-controlled.

Conclusions

These are exciting times in ovarian cancer research and, more importantly, for patients. Recent discoveries have realized the possibility that this is the beginning of the end of ovarian cancer.

Our new understanding of the origins of this disease may give rise to a reasonably effective early detection assay, which remains the holy grail of ovarian cancer research.

The molecular analysis of ovarian cancers with different histologies will allow us to begin to stratify patients appropriately to maximize efficacy and minimize toxicity.

The emergence of new, effective agents, such as antiangiogenics and PARP inhibitors, has brought on the dawn of a new era for ovarian cancer — one in which it is conceivable to begin to whisper about the possibility of curing patients or, at the very least, better managing their disease so as to convert a lethal disease into a chronic one.

This article was published by Healio.

BRCA Mutation, Preventive Surgery, and Osteoporosis

By Kristen Monaco

Researchers advocate for increased hormone therapy for high-risk women.

Bone health suffered in women with a BRCA mutation who underwent preventive oophorectomy, Canadian researchers reported.

Premenopausal women with the BRCA1 or BRCA2 mutation experienced a significant decline in bone mineral density (BMD) after undergoing prophylactic bilateral salpingo-oophorectomy, said Joanne Kotsopoulos, PhD, of the Women’s College Research Institute in Toronto, and colleagues.

Their study online in JAMA Network Open showed the following BMD reductions:

• Lumber spine: annual change -3.45% (95% CI -4.61% to -2.29%)
• Femoral neck: -2.85% (95% CI -3.79% to -1.91%)
• Total hip: -2.24% (95% CI -3.11% to -1.38%)

“These pre-menopausal women looked a lot like post-menopausal women after a year following surgery,” co-author Elizabeth Hall, HBSc, also of the Women’s College Research Institute, previously told MedPage Today at last year’s American Society of Clinical Oncology annual meeting.

During the nearly 2-year follow-up, similar bone changes were seen among women who were postmenopausal at the time of oophorectomy, although this population didn’t see a significant change in total hip bone density (annual change -0.18%, 95% CI -0.82% to 0.46%):

• Lumber spine: annual change -0.82% (95% CI -1.42% to -0.23%)
• Femoral neck: -0.68% (95% CI -1.33% to -0.04%)

However, use of hormonal therapy was able to offset most of the deleterious bone changes in both pre- and post-menopausal women after surgery. Compared with women who didn’t self-report use of any hormones, women who used hormonal therapy saw significantly less changes in BMD annually in the lumbar spine (-2.00% vs -4.69%) and total hip (-1.38% vs -3.21). Loss of BMD in the femoral neck was also mitigated in hormone users, although it did not reach statistical significance (-2.32% vs -3.32%).

Prior to surgery, only 4% of the total cohort were considered to be osteoporotic, while 41% of the women met the World Health Organization’s criteria for osteopenia. After surgery, the proportion of women with osteoporosis and osteopenia jumped significantly to 6% and 54% of the cohort, respectively.

“There are no standardized guidelines for the management of bone health in this population after surgery,” the researchers wrote. “Although [hormone therapy] minimized the amount of BMD loss, it did not completely prevent postsurgery bone loss,” they continued, emphasizing that these findings “strongly support” routine BMD screening in this particularly high-risk population of women.

“There are no standardized guidelines for the management of bone health in this population after surgery,” the team noted.

“Given the important role of estrogen in maintaining various physiological functions, including bone health, this rate of hormone therapy use is far too low,” the researchers stated, suggesting that the “mitigating effects” of hormone therapy use in this population should be noted in future clinical practice guidelines. Specifically, Kotsopoulos, et al. suggested recommending enough calcium intake for this population, as well as engaging in weight-bearing exercise and exogenous hormone use for those for whom it is not contraindicated.

Given that the average age of women who had elective oophorectomy was 48, the researchers said the findings linking estrogen deprivation to deleterious bone health are “not surprising.”

Among the 95 women included in the retrospective cohort study, 83% elected to undergo prophylactic bilateral salpingo-oophorectomy plus hysterectomy, while 17% had bilateral salpingo-oophorectomy only. About half of the women carried the BRCA1 mutation, and the other half possessed the BRCA2 mutation. All individuals included in the study had to have at least one intact ovary prior to surgery and have no history of cancer besides breast cancer.

While only 3% of the total cohort were current hormone therapy users at the time of surgery, 28% opted for hormonal therapy postoperatively. Hormone use was found to be significantly more common among women who were premenopausal at the time of oophorectomy. Similarly, there was an increase in the use of selective estrogen receptor modulators after surgery, although this is more common in those who were postmenopausal at the time of surgery, the team noted.

Furthermore, there was an uptake in use of calcium supplementation, as well as vitamin D supplementation, with similar rates of uptake among both pre- and post-menopausal women.

In comparing their study to prior research in this area, Kotsopoulos and colleagues said they found it “striking” that bone disease screening is not considered routine practice for patients possessing a BRCA mutation.

“Interventions to reduce bone disease (and other adverse noncancer outcomes, including cardiovascular disease or cognitive decline) are necessary and may include a combination of [hormone therapy] use or lifestyle interventions, such as physical activity or supplement use,” the authors urged.

They also recommended special care for these patients, taking into account any treatment with endocrine disruptors, including radiation, chemotherapy, or aromatase inhibitors, which also may negatively affect bone health.

Hall said that future studies with a longer follow-up period are needed to truly estimate the impact of prophylactic bilateral salpingo-oophorectomy on fracture risk in this high-risk population of women.

This article was published by Medpage Today.

Germline BRCA2 Mutations Linked to Pediatric Lymphomas

By Leah Lawrence

In addition to putting carriers at increased risk for breast and ovarian cancers, BRCA2 germline mutations carriers are also at increased risk for pediatric and adolescent non-Hodgkin lymphoma (NHL), according to data from the SJLIFE study.

Survivors of NHL should be offered genetic counseling.

Prior data from the study showed that BRCA2 was the third most frequently mutated gene among 3006 survivors of childhood cancers, with the highest incidence among survivors of lymphoma. To investigate this connection further, researchers conducted whole-genome sequencing on 1380 5-year survivors of pediatric or adolescent lymphomas. Median age at diagnosis was 13.4 years.

Among these survivors, 12 pathogenic or likely pathogenic BRCA2 mutations were identified, a rate of 0.6% among Hodgkin lymphoma survivors and 1.4% among NHL survivors. All 8 survivors of NHL with a BRCA2 mutation were male.

Compared with a group of controls without cancer, survivors with BRCA2 mutations were at more than 3 times the risk for lymphoma (odds ratio, 3.3; 95% CI, 1.7-5.8). When looked at by specific diagnosis, only the association between the aberration and NHL was statistically significant (OR, 5.0; 95% CI, 2.1-10.2).

When family histories were obtained for 7 of the 8 NHL survivors with BRCA2 mutations, 6 were found to have family histories of breast, prostate, and pancreatic cancers, as well as melanoma.

“Genetic counseling and the option of BRCA2 genetic testing should be offered to survivors of pediatric or adolescent non–Hodgkin lymphoma, particularly those with a family history of BRCA2-associated cancers,” the researchers wrote. “Survivors whose test results are positive for mutation should be offered surveillance for BRCA2-associated cancers, such as breast and ovarian, and counseled about cancer risk–reducing strategies.”

This article was published by Cancer Therapy Advisor.

Ribociclib-Letrozole Regimen Tested in Ovarian, Endometrial Cancer

By Dave Levitan

A phase II study found that the combination of ribociclib and letrozole showed promising activity in patients with estrogen receptor-positive ovarian cancer and endometrial cancer. The most benefit was observed in low-grade serous ovarian cancers.

“Up to 60% of ovarian tumors can be estrogen receptor (ER)-positive,” said Gerardo Colon-Otero, MD, of the Mayo Clinic in Jacksonville, Florida.

Previous trials of aromatase inhibitors in ovarian and endometrial cancer have been disappointing, but recent work showing good results when combined with cyclin kinase inhibitors, such as ribociclib, led to the new trial. Colon-Otero presented results of the study at the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting, held May 31-June 4 in Chicago (Abstract 5510).

The phase II trial included 20 women with ER-positive ovarian cancer and 20 with ER-positive endometrial cancer. All patients received letrozole 2.5 mg daily and ribociclib 400 mg daily; they were treated until progression or unacceptable toxicity.

The median age in the ovarian cancer cohort was 61 years; in the endometrial cancer cohort, it was 64.5 years. Most patients in both cohorts had a performance status of 0, and most of the cohorts were white. Ovarian cancer patients had a median of three previous chemotherapy regimens; for those with endometrial cancer, the median was two previous regimens.

The study’s primary endpoint was met, based on the percentage of patients still alive and progression-free after 12 weeks (PFS12). The PFS12 in the ovarian cancer cohort was 50%, and 25% (five patients) were progression-free at 23 weeks. In the endometrial cancer patients, the PFS12 rate was 55%, and 45% were progression-free at 23 weeks.

Patients with low-grade serous ovarian cancer appeared to derive the most benefit, as all three patients were progression-free for at least 23 weeks; in fact, those three patients remained on therapy for more than 28, 24, and 19 months, respectively. Only 2 of the other 17 patients (12%) with ovarian cancer were progression-free at 23 weeks.

In the endometrial cancer patients, the most benefit was seen in those with grade 1–2 disease; 64% of those patients were progression-free for at least 23 weeks, compared with 22% of those with grade 3 disease.

The median PFS was 2.8 months in the ovarian cancer cohort, and 5.4 months in the endometrial cancer patients. The median overall survival in the two cohorts was 18.9 months and 15.7 months, respectively.

The most common treatment-related serious adverse events (AEs) included leukopenia (17.5%), neutropenia (15%), lymphopenia (7.5%), liver enzyme elevations (7.5%), and fatigue (5%). These were grade 3 AEs, with the exception of one case of grade 4 lymphopenia. There were no grade 5 AEs.

“Additional studies of this combination are indicated in ER-positive low-grade serous ovarian cancer, and grade one and two endometrial cancers,” Colon-Otero concluded.

Helen Mackay, MD, of the Princess Margaret Cancer Center in Toronto, discussed the study for ASCO. She agreed that these are “interesting data” and that larger, randomized trials are warranted. She noted, though, that some outstanding questions about the approach remain.

“Are the aromatase inhibitors the same in endocrine and gynecologic cancers as in breast?” she asked. “What’s going on in these pathways?… I’d encourage people to address the fundamental questions before moving into toxic combinations.”

This article was published by Cancer Network.

Discovery of New “Don’t Eat Me Protein” Points the Way to Effective Cancer Therapy

By Alexandru Micu

Stanford University (SU) researchers have found a new signaling molecule that cancer cells use to keep the immune system at bay.

Our bodies’ immune cells are, among other objectives, tasked with clearing out malfunctioning cells. In theory, cancer cells fall into this category and should be targeted; in practice, however, they use all sorts of biochemical tricks to avoid detection. Researchers at the SU School of Medicine have identified a new signaling molecule that cancer cells use for this purpose.

Cloaking proteins

Immune system cells called macrophages normally detect sick or damaged cells, then proceed to engulf and devour them. In recent years, however, researchers have discovered that proteins on the cell surface can tell macrophages not to destroy them. While this mechanism is meant for good, law-abiding cells to keep the immune system from attacking them, cancer cells have hijacked the same mechanism.

The authors’ past research has shown that the proteins PDL1 and CD47 are used by cancer cells to hide from immune system cells. The discovery of these two proteins and their role also pointed to a possible treatment against cancer: blocking them to ‘uncloak’ cancer cells. Antibodies aimed at blocking CD47 undergoing clinical trials, while treatments targeting PDL1 are already in use in oncology clinics. 

“Finding that not all patients responded to anti-CD47 antibodies helped fuel our research at Stanford to test whether non-responder cells and patients might have alternative ‘don’t eat me’ signals,” said co-author Irving Weissman, the Virginia and D.K. Ludwig Professors for Clinical Investigation in Cancer Research.

The team reports finding a new such protein, called CD24, that cancer cells employ as a “don’t eat me” sign. They began by looking for proteins that were produced in larger quantities in cancer cells than in the surrounding, healthy tissues. The hypothesis the team was working on was that cancers growing in the presence of macrophages need to produce some kind of signaling molecule to keep themselves safe. This should be reflected in a higher concentration of that particular compound in the cancer cells — and, by disrupting this compound, cancer could be made vulnerable.

Many different types of cancer produce higher levels of CD24 compared with normal cells and surrounding tissues, the team explains. They further showed that macrophage cells which infiltrate the tumor sense the presence of this protein through a specialized receptor (SIGLEC-10). They placed a mix of cancer cells harvested from patients and macrophages in a dish and then blocked the interaction between CD24 and SIGLEC-10. The macrophages immediately started breaking down the cancer cells, they explain. Lastly, they implanted human breast cancer cells in mice and blocked CD24 signaling — the mice’s macrophages attacked the cancer cells, the team reports.

Of particular interest was the discovery that ovarian and triple-negative breast cancer, both of which are very hard to treat, were highly affected by blocking the CD24 signaling.

“This may be a vulnerability for those very dangerous cancers,” said Amira Barkal, an MD-PhD student and lead author of the paper.

CD24 seems to often work as a complement to CD47 — one of the previously-identified ‘don’t eat me’ proteins — the team adds. Some cancers, like blood cancer, are highly susceptible to CD47-signaling blockage but not to CD24-signaling blockage. Others, like ovarian cancer, show the exact opposite susceptibility. This finding makes the team confident that most (if not all) types of cancers can be attacked by blocking one of these two signaling molecules.

The researchers now hope that therapies to block CD24 signaling will follow in the footsteps of anti-CD47 therapies, being tested first for safety in preclinical trials, followed by safety and efficacy clinical trials in humans. In the future, they plan to keep sniffing out such proteins in a bid to make cancers even more vulnerable by blocking several ‘don’t eat me’ proteins at a time.

“There are probably many major and minor ‘don’t eat me’ signals, and CD24 seems to be one of the major ones,” Barkal said.

Combined with novel ways of detecting the disease, such treatment avenues may finally spell the end of cancer as we know it today. Not a day too soon.

The paper “Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy” has been published in the journal Nature Immunology.

This article was published by ZME Science.