1. Gallagher, Amy

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While genetic signature cancers may help predict the risk of recurrence, possibly even identify a more effective treatment strategy, current practice guidelines recommend chemotherapy determined by risk as opposed to predictive factors. One notable and potent predictive marker exhibited in about 25 percent of all breast cancers is the phosphoinositide 3-kinase (PI3K)-activating mutations widely known for their responses to P13K inhibitors.

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Targeting therapeutic strategies to treat triple-negative breast cancer (TNBC) prompted research that was presented during the 2021 San Antonio Breast Cancer Symposium by Nandini Dey, PhD, MS, Director and Senior Scientist lead at of the Translational Oncology Laboratory, and Pradip De, PhD, MS, Senior Scientist in the Translational Oncology Laboratory, both at Avera Cancer Institute.


"With the increased technology of advanced genomics, molecularly driven precision medicine, and immunotherapy, a cancer diagnosis is no longer the death sentence it once was," De said. Metastatic cancers, including TNBC, are hugely complex, individually distinct, and constantly evolving, he noted.


"We tested our hypothesis that a synthetic lethal approach can be successful by using a combination of DDR and PI3K pathway inhibitors in HR-deficient tumors co-harboring alterations in the PI3K pathway genes," De explained.


Hypothesizing the contextual cooperation between the cellular signals of the PI3K and DDR pathways, the researchers sought to identify the co-alterations of the PI3K and DDR pathway genes in the TNBC patient cohort to: 1) interrogate the contextuality of such alterations, and 2) understand the mechanism of the contextual cooperation using an algorithmically chosen combination of pathway targeted drugs. The targeted drug used in the study was poly-adenosine diphosphate-ribose polymerase (PARP), an enzyme that helps repair DNA damage in cells. PARP inhibitors are now the standard of care for TNBC and ovarian cancer patients, De noted.


"PARP inhibitors demonstrate efficacy in tumors harboring aberrations in the DNA-damage repair pathway gene(s) with limited activity," he said. "Single-agent targeting of the PI3K pathway has shown effects limited to ER+BC."


Since a good number of patients with TNBC harbor co-alterations in the DNA damage and PI3K pathways as presented in the study, there exists a clear unmet clinical need to test the use of combination therapy (PARP inhibitor + PI3K pathway inhibitor) to expand the depth and durability of the treatment response, De explained.


Validating Two Pathways

The researchers presented an algorithm for a rational combination of the PI3K and the DDR pathway targeted drugs in TNBC.


"In breast cancers, alterations of the PI3K pathway genes are both subtype-specific, as well as contextual," Dey explained. "The PI3K pathway signals not only for cell survival and proliferation in tumor cells, but also controls DNA-DDR and maintains HR (homologous recombination) steady-state translational significance."


Alterations of DDR pathway genes are one such contextual event occurring with the upregulation of the PI3K pathway, she said.


"After analyzing the somatic alterations' profile of genes in 264 breast cancer patients and to demonstrate the efficacy of a combination of node-specific targeted inhibitor(s), we experimentally validated the cooperation between the two pathways using alteration-guided targeted inhibitors-isoform-specific PI3K and PARP inhibitor(s) in the TNBC model," Dey noted. "PARP inhibitors work by preventing cancer cells from repairing, causing those cells to die."


Results of the Trial

The predominant type of mutation of genes in the PI3K pathway in the patients with TNBC was found in PTEN (Y68C, Y180*, loss, loss exons 1-5, and deletion exon1) and PIK3CA (amplification, E545K, H1047R). The other common mutation found was in TP53 (>80%) and somatic BRCA1/2 (~15%) genes. The interaction between the two pathways was evaluated, applying STRING10 to test the association at the highest 0.900 confidence views.


The highest level of drug efficiency is demonstrated following the treatment of p110[beta] inhibitor (AZD 6482) in combination with a PARP inhibitor (olaparib/talazoparib) in BRCA-incompetent PTEN-null TNBC cells (SUM149), as compared to the efficiency of a combination of a PI3K pathway targeted inhibitor (p110[alpha]) with a PARP inhibitor plus DNA damaging agent (carboplatin) in BRCA-competent PTEN WT but PIK3CA-altered TNBC cells (BT20).


The context-dependent synergy between the PI3K and DDR pathways in the TNBC model is comprehended at the levels of load of DNA damage, PARP activity, BRCA1/2 competency or HRD scores, and mode of upregulation of PI3K pathway.


Future Research Studies

"Testing the drug combination(s) in a more appropriate model is imperative than on cell lines or in vivo animal models," Dey noted. "Keeping in mind the unique nature of the tumor and the response of the tumor cells to a drug combination in each patient, we plan to expand the work in the future by testing the combination in a real-life situation in an ex vivo model as we prepare to open a clinical trial."


The researchers drug testing platform will be based on genomic alterations of tumors from an individual patient(s). "Our model will provide a unique opportunity to conduct an experimental snapshot test (drug combinations) on an individual patient's resected tumor(s) while tracking the evolution of the disease in a particular patient, we plan to include data from patients' longitudinal real-time CTC as a non-invasive liquid-biopsy readout as the long-term surveillance," Dey concluded.


Amy Gallagher is a contributing writer.