Plenary highlights critical cancer drivers and novel therapeutic opportunities
Understanding of the drivers of tumor initiation and progression has significantly evolved over the past decades, as has appreciation of the therapeutic landscape.
During the Tuesday, April 13, plenary session Cancer Biology and the Changing Therapeutic Landscape, several speakers spoke on topics that delved into the continued importance of targets residing within incipient tumor cells. Registrants can watch a replay of the Plenary Session anytime through June 21, 2021.
William George Kaelin, Jr., MD, FAACR, Dana Farber Cancer Institute, highlighted the critical role hypoxia plays in tumor growth and progression.
“Some of the mutations that occur late during the evolution of a given tumor, whether driver or passenger mutations, are only tolerated, yet alone advantageous to the tumor, because of mutations that preceded them,” Kaelin said. “If that is true, then correcting earlier mutations should selectively kill tumor cells by unmasking these otherwise potentially deleterious effects of these late mutations.”
Kaelin focused on the von-Hippel Lindau (VHL) tumor suppressor gene, which is frequently an initiating event in kidney cancers, and changing thoughts around the idea of undruggable targets.
For example, Kaelin discussed role of hypoxia inducible factor HIF2α in the development of kidney tumors and its role as a target in VHL-defective kidney tumors. HIF2α, being a DNA transcription factor, was viewed as undruggable, Kaelin said. Previously, researchers worked around this by going downstream to other targets, including vascular endothelial growth factor (VEGF). However, not all patients with VHL-mutant kidney cancer respond to VEGF inhibitors, and those who do will eventually progress.
That led researchers to continue focusing on HIF2α itself. With further research, an HIF2α inhibitor was developed. Preclinical models showed that when administered to VHL-mutant kidney cancer cell lines, the inhibitor decreased HIF-dependent mRNAs, decreased ability to proliferate, and decreased tumor growth.
Eventually, a second-generation HIF2α inhibitor went into clinical testing in a phase II trial. Results of that trial showed that a group of heavily pretreated patients benefited, and a phase III trial has been initiated. But Kaelin pointed out that some patients did not benefit, meaning more research is required.
Tony Hunter, PhD, FAACR, Salk Institute, discussed leukemia inhibitory factor (LIF) and its role in pancreatic ductal adenocarcinoma (PDAC) progression. His research has focused on LIF for several reasons including that the pancreatic cancer associated fibroblast (CAF) secretome contains high LIF levels, suggesting it might be important, and that high LIF mRNA expression levels correlate with poor early stage PDAC prognosis.
Hunter and colleagues carried out preclinical studies on the role of LIF in PDAC in a KPC mouse PDAC model and found that LIF RNA is high in stromal cells adjacent to tumor cells and that LIF receptor is expressed in tumor cells and not stromal cells.
A number of human pancreatic cancer cell lines have also been shown to secrete LIF, and LIF has been detected at elevated levels in the serum and plasma of human PDAC patients. Additionally, studies showed that circulating LIF could be used as a PDAC biomarker, a complement to CA19-9.
“LIF has been implicated not only in pancreatic cancer, but also in breast cancer, glioblastoma, prostate cancer, ovarian cancer, and osteosarcoma, as well as being involved in cancer cachexia,” Hunter said. “This raises the question of whether LIF can be targeted in human pancreatic cancer and other cancers.”
Olufunmilayo I. Olopade, MD, FAACR, The University of Chicago, highlighted important work that has led to the identification of high-risk genetic factors that must be taken into account when monitoring patients but that also hold promise to identify how to personalize therapeutic options that target the varied components of the tumor tissue.
Olopade discussed her and colleagues work in getting to the root of breast cancer by studying women across the African diaspora and understanding why Black women have the highest death rate from breast cancer. She discussed was a study designed to find if there were additional germline variants associated with somatic mutational signatures and immune-related pathways in women with breast cancer, in order to identify therapies that could be combined for treatment. The study identified association between germline variants and mutational patterns in breast cancer across diverse populations and geography.
Olopade also discussed how genome wide association studies (GWAS) led to the identification of the flip-flop phenomenon, where risk allele found in one population becomes protective in another racial population.
Continued studies into these population differences have identified that not only BRCA1, but things like WNT-β-catenin, telomere stability, and others all play a role and may be mediating how patients tolerate treatment or how quickly tumors progress.
“After this pandemic, we have to think about equity. We have to see how we can have precision health care where we can use telehealth for comprehensive risk assessment because, of course, you are born with genes and they are there until you develop cancer,” Olopade said. “We can’t wait until you develop cancer to understand how we use GWAS and loci and other rare variants that may be responsible for treatment.”
New treatment paradigms
Dennis J. Slamon, MD, PhD, FAACR, University of California, Los Angeles, talked about exploiting cancer biology to develop new treatment paradigms. Using breast cancer as an example, Slamon discussed the heterogeneity that exists within cancer types and how this molecular diversity carries biologic and therapeutic implications.
Harnessing this molecular diversity is well illustrated with the example of HER2 amplification or overexpression and HER2-targeted therapies such as trastuzumab, which have reversed the natural history of the disease. Slamon also discussed some new and novel strategies in this patient population, including the use of dual HER2 antibody blockade, antibody drug conjugates such as trastuzuamb deruxtecan, and the tyrosine kinase inhibitor tucatinib.
In estrogen-receptor (ER)-positive breast cancer, CDK4/6 inhibitors have changed the treatment landscape. Hormone receptor positive breast cancers were traditionally treated with SERMS, aromatase inhibitor or anti-estrogens. Clinical trials of CDK4/6 inhibitors showed remarkable outcomes data, with the largest change in progression-free survival seen in ER-positive breast cancer in the last four-and-a-half decades, Slamon said.
Subsequent trials also showed improvements in overall survival when this class of drugs was added to anti-hormonal therapy. Preclinical studies now explore combining CDK4/6 inhibitors with anti-HER2 drugs in ER-positive HER2-positive disease.