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Targeted Cancer Therapies

Targeted Cancer Therapies

What are Targeted Cancer Therapies?

Targeted cancer therapies use drugs to more precisely identify and attack cancer cells, based on a person’s genes, as compared to traditional cancer treatments. As such, targeted cancer therapies are sometimes called “molecularly targeted drugs” or “molecularly targeted therapies” and allow for a more precision medicine approach.

In addition to being molecularly-focused, targeted therapies are often cytostatic (which means they block tumor cell proliferation), whereas standard chemotherapy agents are cytotoxic (which means they kill tumor cells). Therefore, many targeted drugs go after the mechanisms that make cancer cells different than normal cells and leave the healthy cells alone.

NFCR Research Highlights

Dr. Daniel Von Hoff is developing monoclonal antibodies (Mabs) that target a key protein in the fibrotic or ‘stromal’ cells that surrounds many types of tumors. When the protein is inactivated when bound by the Mab, it can no longer signal to the tumor cells to metastasize from the primary tumor. With funds from the NFCR AIM-HI Translational Research Initiative, the best monoclonal antibodies are in final pre-clinical stages and the most promising one may soon enter clinical trials to treat colorectal cancer patients who need a new effective treatment to save their lives.

The immunotherapy called ‘checkpoint inhibitors’ is revolutionizing treatment for some cancers but it is not effective in the aggressive brain cancer, GBM. Dr. Rakesh Jain is using treatments to target factors in abnormal blood vessels combined with the checkpoint inhibitors to successfully stop cancer growth in complex models of GBM. The combination approach has high potential to improve treatment outcomes and increase survival in GBM patients.

Dr. Cesare Spadoni’s team is developing treatments for childhood cancers. In the brain cancer, medulloblastoma, research is identifying the most promising drug or a drug combination that inhibits two targets in pre-clinical models of medulloblastoma. The scientists have also determined that the small molecule, volasertib, serves as an effective treatment for the pediatric soft tissue sarcoma, rhabdomyosarcoma. Volasertib targets and inhibits an enzyme resulting in reduced expression and activity of two abnormal fused genes responsible for causing rhabdomyosarcoma. With NFCR support, Dr. Spadoni’s efforts have led to this promising therapeutic now being commercialized through the AIM-HI Translational Research Initiative. To learn more, click here.

With support from the NFCR AIM-HI Translational Research Initiative, Dr. Ronald DePinho and colleagues have developed a promising new drug that targets one of the major signaling proteins in over 50% of cancers. The protein, STAT3, controls networks of genes for numerous cellular processes, such as proliferation, survival, angiogenesis, metastasis, invasion, and immune escape. The drug is now in Phase 1 clinical trials to treat various types of advanced cancers.

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Wei Zhang: The Art of Precision

“The essence of precision medicine, in particular precision oncology, is to make cancer management more precise based on genomic mapping and molecular characterization of the unique tumors for each patient,” says Dr. Wei Zhang. “The cancer management that needs to be precision include diagnosis, prognosis, treatment plan, treatment monitoring, and genetic counseling.” Precision medicine, and by extension, oncology, is the buzzword of the moment among doctors and researchers, and it is more than just spin or a fad. With regards to cancer, and as our understanding of the disease has increased, the idea of a one-drug-cures-all panacea is now widely considered obsolete (however much of a holy grail such would be). Cancer, even the same type, varies at a genetic level from patient to patient. The therapies that work with “Patient A” may not at all with “Patient B,” due at least in part in the natural genetic difference that exists among practically all living things. Zhang admits the field is still in its infancy, the promise it holds is vast: with the rise of genomics, scientists can untangle the genetic knot of cancer, tailoring customized treatment regimens unique to a person, start to finish. Trailblazing cancer research for the last 20 years, Zhang has been witness to the evolution of cancer treatment, at one point co-directing a Genome Data Analysis Center under the National Cancer Institute-funded Cancer Genome Atlas program. He also served as Director of the Cancer Systems Biology Center funded by the National Foundation for Cancer Research for several years when at the MD Anderson Cancer Center. In 2016, he was recruited to the Wake Forest Comprehensive Cancer Center located in Winston Salem, North Carolina to lead the Center for Cancer Genomics and Precision Oncology and takes a direct role in the development of targeted therapies. Moreover, Zhang, who is also an NFCR Fellow, instituted sorely-needed diversity in cancer research. While cancer is not particularly picky, some forms of it tend to show up more in specific ethnicities that, historically, were overlooked, often with great detriment: African-Americans have the highest death rate and shortest survival of any racial and ethnic group in the USA for most cancers. “Our precision medicine/oncology considers health disparities a priority issue of our cancer center,” Zhang explains. “In our program, 14 percent of all cancer patients who are enrolled in our precision oncology trials are African-American patients, a percentage that is much higher than most cancer centers in the country. We have taken on a leading role in our effort in understanding the unique genomics features for cancer of African-American ancestry.” For all its promise, Zhang stressed that precision medicine, and oncology, is still in its infancy. The single most rate-limiting challenge is the effective matching of genomic mutations with corresponding drugs. That being said, precision medicine/oncology is for everyone involved in cancer management. That includes patients and family members, doctors, researchers, pharmaceutical companies, funding agencies and insurance industries.  Decisions have to be made through better research and better development of targeted therapeutics. Zhang is optimistic. “The efficacy will continue to improve with the effort of national consortium such as Precision Medicine […]

Brian Leyland-Jones: Now Is the Time!

“This is the transformative time in oncology,” heralds Brian Leyland-Jones, M.B., B.S., Ph.D., and there is no spin doctoring in the statement by the member of the National Foundation for Cancer Research’s scientific advisory board. From genomics to targeted therapies to vaccinations, the last 40 years has seen more strides in oncology than nearly all the years before them. And Dr. Leyland-Jones has contributed greatly to paving the road. He helped develop drugs that are now mainstays of oncological breast cancer treatment (such as the anthracycline, antimetabolite and platin families), as well as the targeted therapies trastuzumab (sold as Herceptin) and bevacizumab (Avastin). He also helped disprove some theories about how to best treat breast cancer patients. For example, he demonstrated that two years of adjuvant trastuzumab was no better than the standard one year of treatment for women with HER2-positive, early-stage breast cancer. Not bad for a guy who started medicine in a completely unrelated field. “I started doing cardiothoracic surgery,” he recalls. “I had a very close girlfriend at the time who was an oncologist. And one evening she asked, ‘Brian, why do you keep on pursuing cardiothoracic research? Oncology is where the change is.’ And after that point, I thought about it and moved into the field. And her words were absolutely true.” For the record, Dr. Leyland-Jones did not become a world-respected oncologist just to impress a girl; he firmly states that his whole drive was to make the maximum impact in a field. And that he did, becoming Vice-President of Molecular and Experimental Medicine at the Avera Cancer Institute and Director of Precision Oncology in Sioux Falls, South Dakota, and Cancer Center Director at McGill University and the Winship Cancer Institute before that. He and his team’s work with combination targeted therapies and immunotherapies aim to close down the oncogenic drivers of cancer, the cues stemming from mutated genes that ultimately result in tumor formation. He is also pushing the idea of N-to-1 trials, a clinical trial that is of just one person. Even the best cancer therapies tend to paint in broad strokes and disregards the fact the same type of cancer can still vary widely in its response to drugs. Testing patients on an individual basis is not necessarily a new idea — doctors have long prescribed one drug after another for a patient in an effort to monitor efficacy — but such an approach has yet to be standardized. But as oncology, and curative measures in general, moves closer to targeted therapy aimed at individuals and individual subsets within a population, “precision medicine” may become the rule. Dr. Leyland-Jones sees more inevitabilities, such as sequencing the genome of a patient will become routine at diagnosis and that within the decade, CRISPR, a technology that engineers a patient’s existing T cells (the assassins of the immune system) to find and kill cancer cells will be an oncological go-to. Beyond those, he predicts: “I think that the whole immunology field, that is, the immunological approach, to cancer will explode in terms of neoantigen profiling, in terms of vaccines, in terms of a plethora of […]

Targeted Lung Cancer Therapy

A Match Made Possible A discovery by a team led by Massachusetts General Hospital’s Daniel Haber, M.D., Ph.D., a physician-scientist supported by the National Foundation for Cancer Research since 2003, now represents a source of hope for many patients with metastatic lung cancer. He and his colleagues correctly linked very specific epidermal growth factor receptor (EGFR) mutations to a particular subset of non-small cell lung cancer (NSCLC). This breakthrough has made it possible to identify patients who are far more likely to respond well to certain cancer-fighting drugs that block these very EGFR mutations. In 2015, the U.S. Food and Drug Administration (FDA) approved the drug Iressa as a front-line treatment for NSCLC patients with these specific tumor mutations that Dr. Haber had earlier identified. Initially, Iressa (the brand name of the drug gefitinib) was approved for use by the FDA in 2003 as a treatment for NSCLC, broadly. This determination was based on clinical trials which showed a largely across-the-board, albeit modest, positive response rate. However, about 10% of patients had a rapid and often dramatic clinical improvement. The cause remained undetermined as to why these patients responded so particularly well, until Dr. Haber’s groundbreaking study, published in the New England Journal of Medicine in 2004. “In 2003, Iressa was the first EGFR-tyrosine kinase inhibitor (TKI) for patients with non-small cell lung cancer. While some patients showed dramatic benefit, the research at that time did not enable us to identify those patients that would benefit the most from this treatment,” said Gregory Keenan, vice president of medical affairs and U.S. head medical officer of AstraZeneca, the company that developed the drug. “Today, our understanding of molecular mutations and molecular targeting has enabled better decision making in the treatment of NSCLC.” In a normal state, EGFR allows cells to grow and divide at a regular rate. When a mutation causes there to be too many receptors, as happens in cancer, tumorous cells grow and divide uncontrollably. Research studies have shown that genetic mutations can predict whether certain types of drugs—like Iressa—can help treat cancers. The discovery by Dr. Haber’s team means that it is now possible to identify lung cancer patients who are most likely to benefit from Iressa specifically—a textbook example of targeted medicine. When the oncology community hailed the findings as a breakthrough, it was more than just hype: NSCLC is the leading cause of death from cancer in the United States, amounting to over 80% of all lung cancers. Not counting skin cancer, lung cancer (both small cell and NSCLC) is the second most common cancer in both men and women. About 14% of all new cancers are lung cancers, and the death toll from lung cancer alone tops the combined mortality rates of colon, breast and prostate cancers. Chemotherapy slightly prolongs survival among patients with advanced stages of NSCLC, but at the cost of significantly adverse side effects. “Chemotherapy is something of a blunt instrument,” explains Dr Peter Moodie, medical director of New Zealand’s Pharmaceutical Management Agency. “[Iressa’s] kind of targeting is becoming more common with cancer drugs and gives us greater certainty that the people […]