Four scientific highlights from ‘Cellular Bases for Patient Response to Conventional Cancer Therapies’

by Dr. Alexandra Boitor, EACR Scientific Officer

Here are 4 of the most important things we learned at the EACR’s Cellular Bases for Patient Response to Conventional Cancer Therapies conference (Berlin, November 2022). Click here to read what our Travel Grant winners had to say about the conference.

Moving away from the historical cell line-based preclinical explorations, the scientific programme of this conference blended basic and translational research, including data from patient responses and from research performed in mouse models with the aim to better our understanding of molecular pathways involved in cancer response to therapy.

A panel of invited and selected speakers presented their recent, cutting-edge studies investigating the effects of conventional chemotherapy, immunotherapy or hormone therapy directly in patients. Unanticipated, additional modes of action have been discovered, together with unforeseen in vivo-validated cellular effects. Altogether, these disruptive discoveries open novel opportunities for mechanism-based combinations and could therefore be exploited to rethink the use of conventional therapies with the ultimate aim of improving cancer therapeutics.

1Combination therapy could be a fast(er) road towards improving tumour response to treatment.

The conference started with a keynote lecture from Dr Anthony Letai from Harvard University discussing the importance of apoptotic priming for cancer sensitivity to chemotherapeutic agents. Since decreased apoptotic priming via the mitochondrial apoptotic pathway seems to characterise multidrug-resistant relapsed tumours, Dr Letai made a compelling argument for the need to strategically combine cancer therapies in clinical practice [1-4]. Other talks from world-renowned cancer researchers offered further support that such combinations could benefit cancer treatment. For instance, in his talk, Dr. Jean-Emmanuel Sarry highlighted the potential of targeting oxidative phosphorylation to sensitise cells to chemotherapeutic agents. Dr Sarry suggests that treating cytarabine resistant Acute Myeloid Leukemia with a combination of venetoclax/ cytarabine could surpass the cytarabine resistance as venetoclax, a BCL2-selective inhibitor, decreases oxidative stress and primes cells to caspases-dependent apoptosis [5]. Dr Sandra Demaria from Weill Cornell Medicine discussed the benefits of combining radiotherapy and immune-checkpoint therapy. According to Dr Demaria, the DNA damage induced by radiotherapy can lead to the displacement of DNA fragments to the cytosol, which will activate in the tumoral cells and tumour-infiltrating dendritic cells innate and adaptive immune responses normally triggered by viruses (e.g the cGAS/STING pathway). This leads to increased inflammation and attracts T cells to the tumour hence facilitating response to immune checkpoint inhibitor therapy [6-8]. Dr Sophie Pastel-Vinay brought further evidence for the role of DNA damage in tumour immunogenicity. Dr Vinay showed that by increasing inflammation through acting on the cGAS/STING pathway, clinical PARP inhibitors could potentiate the effect of anti-PD-1 therapy in ERCC1-defective Non-Small Cell Lung Cancer and BRCA1-defective triple-negative breast cancer [9, 10].

2Hormonal therapy is not all bad news

During the conference, the role of progesterone and progesterone receptors in breast cancer was discussed highlighting the risks and benefits of hormonal treatments for breast cancer. In his talk, Jason Carroll highlighted the molecular crosstalk between the progesterone and oestrogen receptor pathways and showed that the progesterone receptor can modulate oestrogen receptor binding to chromatin. Dr Carroll also debunked some of the findings of the WHI hormone therapy trials conducted in early 2000, suggesting that hormone therapy benefits may outcome the risks, at least when it comes to breast cancer therapy. Dr Carroll went on to present the PIONEER phase 2 clinical trial that combines standard-of-care oestrogen receptor antagonists, such as letrozole, with progesterone receptor agonists, such as megace, in order to treat cancer by changing the oestrogen receptor activity [11]. On the other hand, Dr Cathrin Brisken’s research suggests that combined oestrogen and progesterone treatment could enhance metastatic spread and suggests that abrogation of progesterone receptor could be a therapeutic option for some patients [12]. These findings however, do not contradict Dr Carroll’s research but rather brings us to highlight #3

3There’s an argument for personalised cancer treatment

In her presentation about the role of progesterone in breast cancer, Dr Brisken highlighted that proliferative responses to combined oestrogen and progesterone administration are patient-specific [12, 13]. In his presentation, Dr Sarry also made a compelling argument for the need to personalise cancer treatments based on the patient’s mitochondrial profile.

4Microbiota influences cancer development

Dr Maria Rescigno explained in her presentation how the pro-tumorigenic gut microbiota can translocate to the liver, where it forms a pre-metastatic niche and promotes the recruitment of metastatic cells

 

In addition to the highlights presented, the conference featured many other very interesting talks that uncovered new mechanisms of action for well-established chemotherapeutic drugs such as oxaliplatin and cisplatin; revealed how resistance to immunotherapy (PARP inhibitors; immune checkpoint inhibitors) develops in some cancers; furthered discussed the involvement of mitochondria in cancer response to treatment and even proposed new therapeutic target candidates.

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References:

  1. Olesinski, E.A., et al., BH3 Profiling Identifies Selective BCL-2 Dependence of Adult Early T-cell Progenitor (ETP) Subtype of Acute Lymphoblastic Leukemia (ALL) Patients. bioRxiv, 2021: p. 2021.08.19.456932.
  2. Pan, R., et al., Augmenting NK cell-based immunotherapy by targeting mitochondrial apoptosis. Cell, 2022. 185(9): p. 1521-1538.e18.
  3. Potter, D.S., et al., Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer. Cell Death & Disease, 2021. 12(8): p. 741.
  4. Sánchez-Rivera, F.J., et al., Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration. Proceedings of the National Academy of Sciences, 2021. 118(23): p. e2019740118.
  5. Bosc, C., et al., Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia. Nature Cancer, 2021. 2(11): p. 1204-1223.
  6. Charpentier, M., et al., Radiation therapy-induced remodeling of the tumor immune microenvironment.Seminars in Cancer Biology, 2022. 86: p. 737-747.
  7. Pilones, K.A., et al., Converging focal radiation and immunotherapy in a preclinical model of triple negative breast cancer: contribution of VISTA blockade. OncoImmunology, 2020. 9(1): p. 1830524.
  8. Rudqvist, N.-P., et al., Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors. 2022, Research Square.
  9. Chabanon, R.M., et al., PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non–small cell lung cancer. The Journal of Clinical Investigation, 2019. 129(3): p. 1211-1228.
  10. Chabanon, R.M., et al., Targeting the DNA damage response in immuno-oncology: developments and opportunities. Nature Reviews Cancer, 2021. 21(11): p. 701-717.
  11. Baird, C.i.D.R. Randomised Phase II clinical trial PIONEER- A Pre-operative wIndOw study of Letrozole plus PR agonist (Megestrol Acetate) versus Letrozole aloNE in post-menopausal patients with ER-positive breast cancer. 2017 – 2022.
  12. Scabia, V., et al., Estrogen receptor positive breast cancers have patient specific hormone sensitivities and rely on progesterone receptor. Nature Communications, 2022. 13(1): p. 3127.
  13. Ronchi, C. and C. Brisken, Targeting the Progesterone Receptor in Breast Cancer: Mind the Short Form! Clinical Cancer Research, 2023: p. OF1-OF2.
  14. Bertocchi, A., et al., Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver. Cancer Cell, 2021. 39(5): p. 708-724.e11.
  15. Mozzarelli, A.M., et al., Abstract 3059: Microbiota mediated CHI3L1 expression as a novel candidate biomarker for breast cancer progression. Cancer Research, 2022. 82(12_Supplement): p. 3059-3059.
  16. Derosa, L., et al., Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Annals of Oncology, 2018. 29(6): p. 1437-1444.
  17. Goubet, A.-G., et al., Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer. Cancer Discovery, 2022. 12(10): p. 2280-2307.
  18. Hakozaki, T., et al., The Gut Microbiome Associates with Immune Checkpoint Inhibition Outcomes in Patients with Advanced Non–Small Cell Lung Cancer. Cancer Immunology Research, 2020. 8(10): p. 1243-1250.
  19. Lee, K.A., et al., Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nature Medicine, 2022. 28(3): p. 535-544.
  20. Routy, B., et al., Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science, 2018. 359(6371): p. 91-97.

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