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Neoadjuvant Immunotherapy Leads to Pathological Responses in MMR-Proficient & MMR-Deficient Early-Stage Colon Cancers

Patients with colon cancer, but no distant metastases yet, can benefit from a short course of immunotherapy while waiting for their surgery, as it can cause tumors to shrink substantially or clear up in a very short time, according to the NICHE study of an innovatory phase II clinical trial (Nat Med 2020; In patients with a specific subtype of colon cancer (MSI), 100 percent of the patients benefited from the therapy. In the other half (with MSS type), 25 percent benefited. Forty patients with two colon cancer subtypes took part in the NICHE study. Twenty of them had the microsatellite-instable (MSI) subtype. Of all patients with non-metastasized colon cancer, 15 percent have this type, and the therapy was effective in all 20 patients. The patients underwent surgery about 4 weeks after the first IV administration. During that short period the vast majority of these tumors had cleared up completely or almost completely. The remaining 20 patients in the NICHE study had microsatellite-stable (MSS) tumors. Tumors of this type, conversely, are known not to respond well to immunotherapy. The researchers found that 25 percent of this group of patients also responded well. Given that 85 percent of all patients with non-metastasized colon cancer have this type, the researchers considered this a hopeful outcome. The NICHE study will continue and the number of patients will be increased. Patients will be monitored for at least 3 years to see whether they remain disease-free.



Structural Basis for Allosteric PARP-1 Retention on DNA Breaks

In a new study, researchers report key structural and biochemical differences among a class of anti-cancer drugs known as PARP inhibitors (Science 2020; doi: 10.1126/science.aax6367). These distinguishing differences were linked to differing capacities of PARP inhibitors to kill cancer cells. The research resolves a longstanding and perplexing quandary over differences between the effectiveness of PARP inhibitors used in cancer clinics. Prior to the study, it was unclear whether PARP inhibitors could also affect the second activity of PARP-1, binding to damaged DNA. The PARP inhibitors that are most effective in the clinic tend to "trap" PARP-1 on DNA, which is thought to prevent cancer cells from dividing. The authors of the study asked whether there could be a structural aspect of PARP inhibitors that increases PARP-1 interaction with DNA. One of these PARP inhibitors, veliparib, decreased PARP-1 binding to DNA and is poor at killing cancer cells compared to other PARP inhibitors. Veliparib thus seems to work against the PARP-1 "trapping" process by weakening PARP-1 interaction with DNA. This result provided a key clue to the puzzle. By comparing the structure of veliparib to clinical PARP inhibitors that do trap PARP-1 on DNA, the authors were able to identify differences in the structures that could account for the ability of the inhibitors to trap versus weaken interactions with DNA. Using veliparib as a starting molecule, the researchers engineered a new PARP inhibitor that did have the capacity to increase PARP-1 interaction with DNA, and this new PARP inhibitor showed greater cancer cell killing relative to veliparib. The results of this study also open up new avenues to designing PARP inhibitors for treating other diseases. While PARP inhibitors used in cancer treatment are selected for their ability to kill cancer cells, there are others used to treat inflammation or cardiovascular disease where the goal is to preserve cells and guard against tissue damage associated with hyper activation of PARP-1. Thus, the ability to tailor PARP inhibitors to reduce PARP-1 trapping on DNA could be important in these applications. The study provides the design principles for tailoring PARP inhibitors to specific applications.



Heritability of Mammographic Breast Density, Density Change, Microcalcifications, & Masses

An analysis of a large Swedish cohort revealed that breast density, microcalcifications, and masses are heritable features, and that breast density and microcalcifications were positively associated with a genetic predisposition to breast cancer (Cancer Res 2020; doi: 10.1158/0008-5472.CAN-19-2455). Researchers evaluated mammographic screening history and detailed questionnaire data from the KARMA prospective cohort study in Sweden. Women were enrolled between January 2011 and March 2013; mammograms were continually collected and participants were followed for diagnosis of breast cancer. Women younger than 40 or older than 75 years were excluded, as were women with a prior breast cancer diagnosis, breast enlargement, or breast reduction. The data cutoff was October 2017. The researchers calculated the heritability of four mammographic features-breast density, average density change per year (cm2/year), microcalcifications, and masses-using 1,940 sister pairs. The heritability of breast density was estimated to be 58 percent, similar to previously reported findings. The heritability of microcalcifications and masses were estimated to be 23 percent and 13 percent, respectively. Breast density change was not determined to be an inherited trait. Researchers investigated the associations between mammographic features and genetic predisposition to breast cancer, as determined by a polygenic risk score (PRS), among 9,365 women in the KARMA cohort. They found statistically significant positive associations between PRS quintiles and breast density and microcalcifications.



Infant High Grade Gliomas Comprise Multiple Subgroups Characterized By Novel Targetable Gene Fusions and Favorable Outcomes

Brain cancer in infants is biologically distinct from other childhood brain tumors and could be successfully treated with targeted drugs, a new study has shown (Cancer Discov 2020; doi: 10.1158/2159-8290.CD-19-1030). In the largest and most comprehensive study of infant gliomas to date, scientists found that these tumors are molecularly different from those in older children, helping explain why they tend to be less aggressive. The new results could help pick out babies with brain tumors who could be spared chemotherapy. The study found that brain tumors in babies often had specific molecular weaknesses which could be targeted by existing targeted drugs-and clinical trials to assess these are now set to open. Scientists carried out a large-scale study of 241 infants from around the world diagnosed with glioma brain tumors. The researchers found that 130 of the 241 tumor samples-or 54 percent-had an entirely different genetic makeup from other forms of childhood brain tumors, despite looking highly similar under the microscope. Some 65 cases, or half of children with the distinct form of infant brain tumors, had specific molecular weaknesses, including ALK and NTRK gene fusions, which can be targeted with existing precision medicines. Next, the team looked at mice with brain tumors caused by ALK gene fusions to compare the effect of a targeted drug, lorlatinib, which works by blocking ALK, with temozolomide chemotherapy. They found that lorlatinib significantly shrunk tumors in seven out of eight mice, or 88 percent, while tumors in mice given chemotherapy kept growing, though at a slower rate. The researchers also grew three-dimensional "mini tumors" in the lab from patient samples and found those that had fusions of NTRK with other genes were particularly sensitive to drugs blocking NTRK. Tumors with these fusion mutations were between two and nine times more sensitive to the targeted treatments entrectinib, crizotinib, and milciclib than those without. A small number of children whose tumors were analyzed in the study were successfully treated with ALK or NTRK targeting drugs, offering further evidence for the promise of targeted treatments for infant brain tumors. Clinical trials are due to open to test the benefit of targeted drugs blocking the ALK and NTRK gene fusions in infant brain tumors-and to better understand the biology of tumors which don't have these faults.