Mary Caffrey

Interest in DNA damage repair (DDR) genes and their role in cancer 

 since 2015, when work in this area won the Nobel Prize in Chemistry. The sheer number of DDR genes—more than 400 are associated with DDR—and the various mechanisms that link DNA repair and DDR signaling proteins to both germline and somatic mutations offer multiple research possibilities.

So, which treatments which will help which types of cancers? A 

 last week during the American Association of Cancer Research (AACR) annual meeting offers a road map, as investigators from EMD Serono Research and Development Institute, Foundation Medicine, and Merck examined 35 of the most common DDR genes across the FoundationCORE database, which includes more than 300,000 genomic profiles.

DNA damage repair refers to processes in which a cell corrects damage to the molecules that pass along a person’s genetic code. Certain types of DDR can lead to cancer if the repair pathways become disrupted or through increased levels of replication stress. Environmental factors are known to trigger DDR.

Fortunately, recent research has also uncovered ways in which these DDR alterations can be disrupted, especially with treatments such as immunotherapy or poly ADP ribose polymerase (PARP) inhibitors. The study presented at AACR sought to map out the most common DDR genes across advanced solid tumor cancers, offering a host of new opportunities to improve outcomes.

According to the abstract the genomic alterations studied included not only the DDR genes, but also complex biomarkers such as tumor mutation burden (TMB), genome-wide loss of heterozygosity [gLOH], microsatellite instability [MSI] status, and PD-L1 expression. The study found that DDR gene alterations are common and unevenly distributed across cancer types; this study included breast, ovarian, colorectal, esophagus, biliary track, gastric, head and neck, pancreas, melanoma, lung, bladder, and prostate cancer.

As expected, TP53 was the most frequently altered DDR gene across the various cancers (59%). Other genes found in more than 1% of cancers were 

 (2%). The remaining DDR genes were rarely altered.

 excluded from the analysis, bladder cancer was most likely to have cases with mutations in DDR genes at 46.59%, while other cancers have rates ranging between 20% and 40%. Researchers are continuing their analysis of the relative distribution of TMB, MSI, gLOH and PD-L1 expression by tumor type and their connection with DDR genomic alterations.

The data analysis is just the beginning, the researchers said

“We systematically analyzed somatic alterations using the Foundation Medicine comprehensive genomic database and provide a comprehensive molecular profiling of DDR deficiencies in advanced solid tumors,” they wrote in the abstract. “It is anticipated that this data will collectively contribute to identify molecularly defined tumor subsets, where single and/or combination therapies such as DDR inhibitors, immunotherapies, targeted therapies etc., may result in increased clinical benefit for patients with cancer.”

Wang D, Elenbaas B, Murugesan K, et al. Comprehensive molecular profiling of DNA damage response (DDR) deficiencies in advanced solid tumors using a real-world genomic database. Presented at the 2021 American Association of Cancer Research Annual Meeting. Abstract 2062; April 10, 2021.

Articles

Interest in therapies that target DDR genes has increased since 2015, when basic science in this area won the Nobel Prize in Chemistry.

Study Uses Foundation Medicine Database to Map Common DDR Genes in Solid Tumors

Following a significant drop in cancer screenings as the pandemic unfolded last year, the Community Oncology Alliance (COA) today announced a partnership to promote cancer screening and catch cancer in its early stages.

The effort, “Time to Screen,” will bring COA together with 

 a nonprofit that serves independent oncology practices and offers patients help with support services meeting financial challenges. The 2 groups will work to connect Americans with screening resources, which can be found at 

. Those who need screening can also call 1-855-53-SCREEN (1-855-537-2733) for information.

“COVID-19 has caused many people to delay recommended cancer screenings, which are now at dangerously low levels. ‘Time to Screen’ is a reminder that everyone can now do something essential for their health,” Kashyap Patel, MD, president of COA and CEO of Carolina Blood and Cancer Care in Rock Hill, South Carolina, 

“It’s safer to get screened now, rather than delaying getting checked for cancer, because early detection catches cancer when it’s most treatable. It may even save your life,” he said.

, led by authors from Avalere Health and COA leadership, found drops in screenings that included an 85% drop in breast cancer screening and a 75% decline in colon cancer screening. Since that time, screening rates have improved somewhat, but average rates for the 4 major cancer types are still down 25% across the country.

 with reports from the National Cancer Institute, whose Director Norman “Ned” Sharpless, MD, said that cancer diagnoses have fallen 50% during the pandemic, with lack of screening being a major reason. It’s not that there is less cancer—it’s not just being diagnosed and treated, and oncologists worry about losing gains made against cancer for years to come.

According to COA, community oncologists report they are seeing the fallout from last year’s delayed or canceled screenings, as cancers diagnosed at later stages demand more complex treatments, resulting in higher morbidity or death. Even if cancer can be successfully treated, the regimens will cost more, which will have an impact on health care costs, especially for Medicare, experts predict. 

The “Time to Screen” campaign provides assistance and educational resources, including the toll-free hotline and website featuring information on screenings for breast, colorectal, cervical, prostate, lung, and skin (melanoma) cancer.

CDC recommendations call for routine screenings for certain cancer types once people reach age 40, and those with a family history of cancer should follow specific recommendations that apply in their situations to offer the best opportunity to detect cancer at its earliest, most treatable stages.

Screening facilities are able to screen patients safely, following guidelines for COVID-19 testing, requiring face covering and social distancing, and limiting the number of people in the facility at any one time.

“Early detection of cancers through regular screenings saves lives. ‘Time to Screen’ connects Americans with local screening options and support to make appointments,” said Patricia J. Goldsmith, CEO of Cancer

. “Through this campaign we will not only be raising awareness of the importance of getting cancer screenings back on track, but also providing important support services to help overcome any barriers that individuals need to access their cancer screenings.”

The campaign will raise public awareness by engaging with local oncology practices, other medical professionals, employers, and health care purchasers. It will also involve multimedia advertising, television and radio interviews, and other strategies. Among those providing support are Bristol Myers Squibb, Genentech, Amgen, Heron Therapeutics, Incyte, Janssen, Pharmacyclics, Daiichi Sankyo Inc, Eisai Inc, EMD Serono, Merck, Pfizer, and Takeda.

Research published in November found an 85% drop in breast cancer screening and a 75% drop in colon cancer screening. Since that time, screening rates have improved somewhat.

COA Launches Effort to Get Cancer Screenings Back on Track

A team of researchers in Indiana has found that the best way to find new treatments for autoimmune diseases, including type 1 diabetes (T1D), is to study the immune system and targeted tissues together, based on an article published earlier this year.

Looking at the immune system in isolation is akin to “attempting to fly a plane with only one wing,” said Decio L. Eizirik, MD, PhD, the scientific director of the Indiana Biosciences Research Institute Diabetes Center, who is the senior author of the paper that appeared in 

The research, funded in part by the JDRF, springs from the fact that autoimmune diseases are increasing worldwide, and the prevalence of T1D, systemic lupus erythematosus (SLE), multiple sclerosis, and rheumatoid arthritis (RA) has reached 0.5% to 5% depending on the region. JDRF’s clinical research strategy has focused in recent years not only on developing treatments and ultimately cures for T1D, but also on preventing it by screening those at greatest risk of developing the disease, and pursuing interventions to halt its onset.

As the authors wrote, “While the immune targets of T1D, SLE, MS, and RA are distinct, they share several similar elements, including common variants that pattern disease risk, local inflammation with contribution by innate immunity, and downstream mechanisms mediating target tissue damage.”

They focused on the increasing evidence that target tissues “are not innocent bystanders of the autoimmune attack, but participate in a deleterious dialog with the immune system that contributes to their own demise.” In their work, the researchers mined RNA sequencing datasets from relevant organ and tissue cells in the different diseases, and identified “similar and dissimilar gene signatures.” In doing so, they identified both candidate genes for the 4 major diseases as well as major common gene expression changes in tissues among them.

One common gene is TYK2, a protein that regulates interferon signaling. The team showed in its research that use of TYK2 inhibitors - already in use for other autoimmune diseases - protect β-cells against immune-mediated damage.

"This research is significant in reaching the JDRF's mission to cure, treat and prevent T1D," Frank Martin, PhD, JDRF director of research, said in a statement. "Discovering the common pathways of tissue destruction across multiple autoimmune diseases will dramatically accelerate our path to a cure for T1D. Drugs that are effective in one autoimmune disease could be equally beneficial for another and quickly repurposed to make a big impact for people living with that disease. Characterizing the similarities and differences between multiple autoimmune diseases has the potential to transform the way we treat and cure these diseases in the future.”

JDRF has undertaken a large-scale screening project, 

, that offers participants a blood test to find antibodies, which tell whether a person is at an early stage of T1D and likely to become insulin dependent. The project comes not only as rates of T1D are rising overall, but as they are rising faster among Black and Hispanic youth. The difference now is that there may soon be a treatment at hand.

showed that the monoclonal antibody teplizumab delayed the onset of T1D

 FDA has scheduled an advisory panel on teplizumab for May 27 and a targeted action date for the drug is set for July 2, 2021.

Szymczak F, Colli ML, Mamula MJ, Evans-Molina C, Elzriki DL. Gene expression signatures of target tissues in type 1 diabetes, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. 

Sims EK, Bundy BN, Stier K, et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. 

. 2021;13:583:eabc8980. DOI: 10.1126/scitranslmed.abc8980

The research, funded in part by the JDRF, springs from the fact that autoimmune diseases are increasing worldwide, and are rising faster among Black and Hispanic youth.

Understanding the Connected Nature of Type 1 Diabetes, Other Autoimmune Diseases

It’s been a year of big news in cholangiocarcinoma. Also called bile duct cancer, this is an aggressive disease of the narrow tubes that carry bile through the liver. Historically, there had been little success with systemic therapy.

But about 4 years ago, research in the disease began to bear fruit, and a breakthrough came a year ago when the FDA granted 

 for pemigatinib. This first targeted therapy in cholangiocarcinoma was approved for previously treated patients with 

 fusions or rearrangements. Other new options, including immunotherapy, have been added to the National Comprehensive Cancer Network 

At this week’s Cholangiocarcinoma Foundation Annual Conference, an extended session on Thursday covered how genomics are driving research into therapeutics for cholangiocarcinoma (CCA). A series of speakers offered updates on the better-known mutations, 

Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center and lead author of the FIGHT-202 trial for pemigatinib, said approval based on the phase 2 study helped patients. Findings showed 107 patients the overall response rate was 36% including 3 complete responses. The median durable response was 9.1 months, with responses lasting at least 6 months in 24 of the 38 patients responding patients (63%) and at least 12 months in 7 (18%) patients.

New targeted therapies are on the horizon; attendees gathered online amid word that FDA had granted Breakthrough Therapy designation to futibatinib, an investigational therapy to treat FGFR2 gene rearrangements, including gene fusions. (A poster on the FOENIX-CCA2 study on futibatinib was presented later in the day).

But the session also shows how work in other 

-mutated cancers is paying dividends in cholangiocarcinoma, with much of the progress coming with familiar drugs, including immunotherapy and PARP inhibitors.

Timothy Yap, MD, associate professor at The University of Texas MD Cancer Center, discussed how the use PARP inhibitors in pancreatic cancer is informing the development of treatments in cholangiocarcinoma. Sarinya Kongpetch, PhD, assistant professor at Khon Kaen University, Thailand, discussed the potential for CDK4/6 inhibitors, which are already FDA-approved in metastatic breast cancer. The “ubiquitous dependency” of cholangiocarcinoma on CDK4/6 activity, Kongpetch said, suggests that the that the CDK4/6-pRB pathway could be a treatable target.

One theme from the speakers and during a panel discussion that followed: the precision medicine approach that is the future of cholangiocarcinoma care demands next-generation sequencing; some called for every patient to be tested for microsatellite instability-high (MSI-H). Challenges going forward will involve developing effective drug combinations: targeted therapies with chemotherapy (and in what order), immunotherapy and PARP inhibitors. Some patients may have more than one druggable target, which will call for individualized care. Only 8000 new cases are diagnosed a year and 5-year survival rates have been low; 10% or less, depending on which type of bile-duct cancer.

are “the best understood mutations to date,” more knowledge is being gained about new potential targets: epigenetic factors 

. Next-generation sequencing is giving researchers new paths to pursue, she said. Said Kongpetch, “

-mutated cancers are sensitive to EZH2 methyltransferase inhibition,” referring to enhancer of zeste homolog 2, which is known to regulate gene expression and is involved in cell proliferation and apoptosis. Development of EZH2 inhibitors is a significant area of cancer research, and Kongpetch said early phase clinical trials said there is particular in interest in evaluating their use in cancers with loss of 

Yap spoke about bringing knowledge gained from other cancers to the fight against cholangiocarcinoma; in particular, he called for deploying PARP inhibitors in combination with immuno-oncology. He outlined a half-dozen classes of DDR inhibitors that have been studied, of which PARP inhibitors have several FDA approvals. He also discussed DDR cell-cycle targets, and what investigators have learned about BRCA-mutated cancers over the 15 years.

“We have learned a lot from pancreatic cancer and use that to apply learnings to every cancer,” he said. The POLO trial involving the use of the PARP inhibitor olaparib for maintenance therapy was “certainly setting the stage for the development of similar agents in biliary cancers,” he said. The challenge is to think about applying inhibitors beyond the 

 scenario, and during them in combinations since drug resistance “is nearly inevitable in patients who do respond initially.”

He showed a chart with PARP inhibitors as the centerpiece of multiple combinations, including radiation. Because of toxicity, however, Yap predicts a move away from chemotherapy combinations to those with PD-1 or PD-L1, or targeted agents and radiation.

 After years of not having options, it appears doctors and patients will have several. In his remarks, Abou-Alfa said accelerated approvals after phase 2, as was done for pemigatinib, are appropriate, given the high level of need, “rather than wait for those elaborate long, pretty evolved studies, or even joined them all in one study, because it will take the same time.”

Otherwise, he said, regulators “really will be missing the point—and missing on the opportunity that we provide for patients.”

Last year, pemigatinib, the first targeted therapy in cholangiocarcinoma was approved for previously treated patients with FGFR2 fusions or rearrangements.

Mary Caffrey

Articles

Study Uses Foundation Medicine Database to Map Common DDR Genes in Solid Tumors

COA Launches Effort to Get Cancer Screenings Back on Track

Understanding the Connected Nature of Type 1 Diabetes, Other Autoimmune Diseases

In Cholangiocarcinoma, New Targets, New Therapies, and Some Old Ones, Too