The $20 million-plus gift from Ludwig Cancer Research proved to be another aturning point for the team. The Ludwig funding allows the team to pursue gene sequencing on a massive scale and, once again, to lead the world in making pioneering cancer discoveries.
The Ludwig Center team had already revealed to the world that cancer was a genetic disease and uncovered some of the genes involved. Now, cancer type by cancer type, they would study every gene in the cancer genome and lay out a specific blueprint of the alterations that caused each cancer to start, grow and spread. “For the first time in the history of medicine, we had the technology to define the mistakes in that genetic code that occur in human cancers,” explains Kinzler.
The discoveries that led the world to understand that cancer is a genetic disease unfolded one by one in the molecular genetics laboratory of Bert Vogelstein, Kenneth Kinzler, Nicholas Papadopoulos, Luis Diaz and Shibin Zhou — since 2006 known as the Ludwig Center at Johns Hopkins.
Vogelstein and his then-student Ken Kinzler discovered the GLI gene through its amplification in advanced forms of brain tumors. The GLI gene and related genes later found by Kinzler and Vogelstein are now known to be the central components of a signaling transduction pathway that contributes to the development of many different forms of tumors.
In a now classic paper published in the New England Journal of Medicine, Vogelstein presented a model for the development of colorectal cancer. The model posited that cancer was a genetic disease driven by sequential mutations in oncogenes and tumor suppressor genes. It has since become the standard icon for understanding human tumors in general.
Vogelstein identified mutations of p53 in colon cancers and showed that it is a tumor suppressor gene. He later demonstrated that p53 is a common denominator underlying many forms of human tumors. These discoveries initiated a revolution in cancer research that continues today, with ramifications for epidemiology, biochemistry, molecular biology and clinical medicine, in addition to genetics. There have been more than 20,000 mutations of p53 discovered since the first one reported by Vogelstein. The p53 gene is the most commonly mutated of all genes ever found in human tumors, including both suppressor genes and oncogenes.
Their studies of inherited colon cancer syndromes lead Vogelstein and Kinzler to identify the cause of an inherited colon cancer syndrome called Familial Adenomatous Polyposis (FAP). They found that this syndrome is the result of hereditary mutations of the APC gene. They soon showed that noninherited (somatic) mutations of this gene initiated colorectal tumors in the general population and caused normal cells to form the precancerous growths known as polyps.
The Vogelstein lab, working with that of Albert de la Chapelle in Finland, discovered that the other major form of hereditary colorectal cancer, hereditary nonpolyposis colon cancer (HNPCC), is caused by a gene on chromosome 3 that disrupts normal DNA repair processes. This seminal finding led Vogelstein’s team and other researchers to clone and identify what are now known as the human mismatch repair genes.
With these discoveries, cancer gene testing was catapulted into mainstream medicine. The Vogelstein lab developed novel tests that could accurately detect the hereditary mutations in a cost-effective and sensitive fashion. This testing is now part of the routine management of patients with strong family histories of colon cancer and has dramatically altered how these patients are diagnosed and treated.
The Vogelstein lab discovered the genes that mediate the effects of the tumor suppressor genes p53, APC and others. These include genes involved in controlling cell growth, such as p21, 14-3-3 sigma, and -catenin, as well as genes controlling cell death, such as PUMA. These studies proved enormously valuable for understanding how genetic alterations are translated into tumor development.
The Vogelstein lab initiated another field of cancer research when they described chromosomal instability (CIN) as a major underlying feature of most human tumors. In addition to outlining the concept, they discovered several genes that promote it in various tumor types.
The Vogelstein lab discovered mutations in PIK3CA, a gene whose product modifies lipids. They showed that mutations in this gene occur not only in colorectal cancers but also in breast, stomach, brain and other tumors. PIK3CA is now recognized to be the most highly mutated oncogene yet identified in human cancers.
The Vogelstein lab developed new tests to detect presymptomatic colorectal tumors on the basis of mutant genes that escape into the stool or blood. They developed highly sophisticated technologies that can detect one mutant DNA molecule among 10,000 normal copies derived from noncancer cells. These tests have the capacity to revolutionize noninvasive testing for colon and other cancers and prevent hundreds of thousands of needless deaths.
Vogelstein and colleagues decoded the genomes for pancreatic cancer and glioblastoma multiforme, a brain cancer. The findings pointed to a group of key pathways in both cancers that can be targets for future therapies. In 2011, the scientists also cracked the genomic code for a rare form of pancreatic cancer, called neuroendocrine or islet cell tumors, and pancreatic cysts, which can be precursors to pancreatic cancer. Investigators working with Vogelstein in the Ludwig Center have also mapped the genomes of ovarian cancer, oligodendrogliomas (a common form of brain cancer), liver cancer and ovarian clear cell cancer.
Vogelstein and colleagues used personalized genome sequencing on an individual with a hereditary form of pancreatic cancer to locate a mutation in a gene called PALB2 that is responsible for initiating the disease. The discovery marked their first use of a genome scanning system to uncover suspect mutations in normal inherited genes. The findings underscored the value of personalized genome sequencing, which decodes a person’s genes and compares the changes to those found in healthy people.
With colleagues in his laboratory, Vogelstein discovered how two cancer-promoting genes enhance a tumor’s capacity to grow and survive under conditions where normal cells die. The knowledge, they say, may offer new treatments that starve cancer cells of a key nutrient: sugar.
Pancreatic cancer develops and spreads much more slowly than scientists have thought, according to research from Vogelstein and colleagues. The finding indicated that there is a potentially broad window for diagnosis and prevention of the disease.
Vogelstein and his Ludwig Center team developed a gene-based test to distinguish harmless from precancerous pancreatic cysts. The test may eventually help some patients avoid needless surgery to remove the harmless variety.
A study involving data of thousands of identical twins by Vogelstein and colleagues found that whole genome sequencing failed to provide informative guidance to most people about their risk for most common diseases, and the team warned against complacency born of negative genome test results.
In a study of 28 advanced colon cancer patients treated with a targeted therapy called panitumumab, Vogelstein and colleagues found that drug resistance mutations appear in the blood of patients about five to seven months after treatment, and low levels of these mutations exist before the therapy begins, making the cancers predestined to recur.
Using cervical fluid obtained during routine Pap tests, scientists in the Ludwig Center developed a test to detect ovarian and endometrial cancers.
January 2014: Bert Vogelstein, M.D., and colleagues received a $90 million gift in new funding from Ludwig Cancer Research, on behalf of founder Daniel K. Ludwig. This gift was part of a larger, $540 million disbursement to five other U.S. institutions.
August 2014: Bert Vogelstein, M.D., and Shibin Zhou, M.D., Ph.D., used a modified version of the Clostridium novyi (C. novyi-NT) bacterium found in soil to produce a strong and precisely targeted antitumor response in rats, dogs and humans.
October 2015: Kenneth Kinzler, Ph.D., was one of 80 new members elected to the National Academy of Medicine. Members of the academy are elected by their peers and advise the U.S. government on medical and health issues.
January 2015: A study led by Ludwig Center scientists finds that random mutations play a predominant role in cancer development.
May 2015: Vogelstein and colleagues find that mistakes in so-called mismatch repair genes, first identified by Johns Hopkins and other scientists two decades ago, may accurately predict cancer most likely to respond to immunotherapy drugs known as PD-1 inhibitors.
June 2015: Ludwig scientists and others from the Johns Hopkins University School of Medicine lead a proof of principle study that successfully identifies tumor DNA shed into the blood and saliva of 93 patients with head and neck cancer.
November 2015: Scientists use gene-based tests and a fixed set of clinical criteria to more accurately distinguish precancerous cysts from those less likely to do harm. The findings may eventually help some patients in real time safely avoid surgery to remove harmless cysts.
July 2016: Vogelstein and colleagues and scientists at the University of Melbourne use a genetic test that spots bits of cancer-related DNA circulating in the blood to accurately predict the likelihood of cancer recurrence in some patients among a small group of patients with early-stage colon cancer.
March 2017: Bert Vogelstein, M.D., and colleagues report data from a new study providing additional evidence that random, unpredictable DNA copying “mistakes” account for nearly two-thirds of the mutations that cause cancer.
April 2017: Ludwig Center scientists win the Team Science award from American Association of Cancer Researchers for the third time since 2013. The award honors their innovations in developing blood tests, or “liquid biopsies,” for cancer.
May 2017: Ludwig Center scientists and others from the University of British Columbia complete a gene sequencing study that reveals unusual mutations in endometriosis. The sequencing may eventually help scientists develop molecular tests to distinguish between aggressive and clinically “indolent,” or non-aggressive, types of endometriosis.
June 2017: Ludwig Center scientists lead a study that adds evidence that flaws in a tumor’s genetic mending kit, known as mismatch repair, drive treatment response to immunotherapy drugs. This research leads to FDA approval of the drug pembrolizumab for patients whose cancers contain the mismatch repair detect. It is the first time a drug has been approved based on a specific genetic profile without regard to where in the body the cancer started.
September 2017: Ludwig Center scientists develop a blood test that spots tumor-specific DNA and protein biomarkers for early-stage pancreatic cancer. Results of the test show that detection of markers from both DNA and protein products of DNA were twice as accurate at identifying the disease as detection of DNA alone.
January 2018: Ludwig Center scientists, led by Nickolas Papadopoulos, Ph.D., pioneered a single blood test that screens for eight common cancer types and helps identify the location of the cancer in the body.
March 2018: Ludwig Center scientists developed PapSEEK and UroSEEK, two new screening test aimed at early detection of cancer. PapSEEK finds cancer DNA from endometrial and ovarian cancers in cervical fluids. UroSEEK finds bladder and urinary tract cancer DNA in urine.