The American Association for Cancer Research Annual Meeting’s Opening Plenary Session: Discovery Science Driving Clinical Breakthroughs featured a broad range of topics—from cutting-edge cell tracking research to advances in our understanding of tumor metabolism to clinical targeting in ethnically diverse populations—illustrating the translational path from basic science discovery to practice-changing treatment.
Registered attendees will have access to watch a replay of the session through June 21, 2021.
cGAS and antitumor response
Zhijan James Chen, PhD, UT Southwestern Medical School, talked about igniting an antitumor immune response with cGAS, a new means of regulating the sensing of DNA in the cytoplasm.
“The DNA-sensing enzyme cGAS is activated by binding with double-stranded DNA, and as the cGAS is activated, it converts GTP and ATP into cyclic GMP-AMP, or cGAMP,” Chen said. “This small molecule then functions as a second messenger that binds to the adaptive protein STING, which is localized on the ER membrane. STING then activates a signaling cascade that leads to induction of type 1 interferons.”
He presented data suggesting strong evidence that the cGAS-STING pathway is very important for innate anti-tumor immune response.
“By better understanding this pathway and by harnessing the power of the cGAS-STING pathway, which is an endogenous innate anti-tumor immunity pathway, new therapies can be developed to benefit patients who currently do not have good options,” he said.
Malignant clonal dominance
Mark A. Dawson, MD, PhD, Peter MacCallum Cancer Center, discussed recent work addressing the significance of transcriptional processes that facilitate malignant clonal dominance in isogenic cancer cells and highlighted emerging evidence showing the importance of manipulating transcriptional regulators to facilitate anti-cancer immune surveillance in a broad range of cancers.
While the evolutionary trajectories and clonal fitness imparted by genetic intra-tumor heterogeneity (ITH) are becoming increasingly clear, Dawson said that little is known about the non-genetic mechanisms that contribute to ITH and malignant clonal fitness.
“Much of our thinking over the last decade has been shaped by information gleaned through the sequencing of bulk cancer genomes and the subsequent inference of clonal competition,” Dawson said. “This has led to models of linear cancer evolution by means of sequential genetic mutations.”
Dawson presented data showing that cancer-initiating cells have a primitive cell of origin and co-opt preexisting transcriptional programs of self-renewal and immune evasion by reduced antigen presentation, and that clonal dominance is an inherent property, regardless of the genotype of the cancer cell, and this determines clonal output and tissue predilection.
“Cell behavior cannot simply be explained by the cancer genome, and really for us to achieve our ambition of precision medicine, we need to study and further develop approaches to tackle non-genetic mechanisms of clonal dominance,” he said.
Genomic sequencing in diverse populations
Over the past decade, genomic advancements have afforded tremendous opportunities in cancer research, said Melissa B. Davis, PhD, Weill Cornell Medical College. But despite these advances, disparities in cancer outcomes persist as does a paucity in data to understand the breadth of diversity in tumor traits across populations.
“African Americans in the U.S. have had the lowest survival rates in nearly all cancers,” Davis said. “We know that socioeconomic status is correlated with survival because poverty impedes the access to health care that is required to survive such a diagnosis. However, what is striking is that when we stratify for race across poor versus affluent counties, we find that African Americans still have the highest mortality burden even in affluent communities compared to their white counterparts.”
Most of the data that defines current understanding of cancer genetics was generated within the context of European ancestry. This bias is partially due to geographic convenience of recruitment within the proximity of the institutions that generate these data elements.
Davis issued a “call to action” emphasizing the importance of including not only the genetic history (ancestry) but also the social history (self-reported race) of cancer patients.
“This multidisciplinary approach will unlock our understanding of the drivers of aggressive tumor biology and be a catalyst for implementation of customized prevention and survivorship interventions,” she said. “Only with the power of inclusion can we hope to traverse the breadth of disparities and make leaps of progress in cancer research and treatment.”
Diet and cancer therapy
Karen H. Vousden, PhD, FAACR, The Francis Crick Institute, and Matthew G. Vander Heiden, MD, PhD, Koch Institute for Integrative Cancer Research at MIT, discussed tumor metabolism and the potential roles for diet in cancer.
“Almost everyone has an opinion about diet and which foods are best and, understandably, when someone is facing cancer there is a lot of interest in making the right diet choices to do what one can to help with their care,” Vander Heiden said. “However, as a physician I can tell you that there is much less data than people think and, in most cases, there is not a clear answer to that question.”
Determining the best diet is like trying to “hit a moving target,” Vousden agreed, but said that there is strong epidemiological evidence to support the association between diet-induced obesity and the development of cancer.
“Interestingly, this isn’t seen for all types of cancer,” Vousden said. “But overall, it’s estimated that 15-20 percent of cancer deaths are associated with obesity, making this a very attractive target for prevention strategies.”
Vander Heiden pointed out that many of the known relationships between whole-body metabolism and cancer that have been uncovered involve hormones, such as insulin and insulin-like growth factors, which are important for regulating glucose levels in the blood and also promote cell proliferation.
“But there is now growing evidence that diet-induced changes in the levels of specific nutrients can also impact the growth of tumors, as well as influence the response to some therapies,” Vander Heiden said.
Following tumor evolution and metastasis
Jonathan S. Weissman, PhD, Whitehead Institute, discussed ongoing work in the development of single-cell “molecular flight recorder” technology that allows researchers to record the history of a tumor in its DNA, reconstruct its phylogenetic tree, and follow its evolution and metastasis.
“This type of phylogenetic analysis is extremely powerful and broadly used in biology,” Weissman said. “Similarly, cancer as an evolutionary process has been broadly informed by these types of phylogenetic analyses. They have allowed us to address questions like how cancer starts, how tumors spread and metastasize, and how tumors evade therapies.”
In their work, Weissman and his colleagues engineered cancer cells to include a neutral part of DNA, or “scratchpad,” which can be targeted by CRISPR-Cas9 over time during the evolution of the tumor.
“This leads to marks in the DNA at different places and with different sequence in the DNA, and, once those marks are made, they are inherited by all the daughter cells and there is opportunity to get further marks as the cells grow and divide,” he said.
Weissman reported that lineage tracing has enabled them to follow the routes and directionality of metastasis and monitor the progression of cancer from oncogenic mutation to aggressive metastatic tumor.