LBCA Scientific Advisory Board member, Dr. George Sflomos, recently published a research article LOX Inhibition Disrupts a Collagen–Integrin–MYC Axis to Suppress Progression of Invasive Lobular Carcinoma. Dr. Sflomos kindly agreed to answer a series of questions from LBCA staff about this particular study, what may come next, and shared that “what excites me most is that this points to a new weakness in lobular breast cancer that comes from its own unique and distinct biology compared to non-lobular breast carcinomas.” He provided a few references at the end for those interested in reading more about different aspects of this research.

Question: What is LOX? Where is it found? Is it something that is present in all ILC cells?

Dr. Sflomos’ Answer: LOX stands for Lysyl OXidase. It is an enzyme that helps organize and strengthen tissues by modifying structural proteins such as collagen and elastin. LOX is not found only in cancer. It is normally present in many normal tissues where the body needs to build, repair, or maintain connective tissue. In cancer, however, LOX and related enzymes can be used in abnormal ways. In invasive lobular breast cancer, or ILC, the findings suggest a particular dependency on the LOX-related tissue remodeling pathway. The work points to a biologically important feature of ILC: many lobular tumors appear to interact strongly with, and partly depend on, the collagen-rich environment around them to grow.

Question: In lay terms, can you explain what “intraductal xenograft models” are? How was it discovered that a drug currently in clinical trials for a rare blood cancer might be effective in treating ILC?

Dr. Sflomos’ Answer: Because we cannot test every biological question directly in patients, we need preclinical models. But preclinical models are not perfect. However, some are useful because they reproduce important aspects of the disease. The important point is to know which model to use for which question. For ILC, we need models that reflect its specific biology, rather than relying only on models developed for other breast cancer types. An “intraductal xenograft model” is a laboratory or “pre-clinical” model in which freshly dissected human breast cancer cells, dissected in the surgical theater, are placed into the milk ducts of a mouse mammary gland. “Xenograft” simply means that cells from one species, in this case human cells, are grown in another species, in this case a mouse. “Intraductal” means that the cells are placed inside the milk ducts, rather than under the skin or in another less natural location that is sometimes used for technical convenience. The microenvironment, that is, what is around the cells, is extremely important because ILC often grows in a very particular way, with cancer cells spreading as single cells or thin strands rather than forming a clear lump. By growing human ILC cells inside the mammary ducts, we better reproduce how ILC behaves in patients.

The link to the drug came from understanding the biology of ILC. Earlier work showed that lobular cancer cells have a distinctive relationship with the tissue structure around them, especially collagen. However, earlier experimental LOX inhibitors are not suitable for clinical use because of toxicity. The drug, PXS-5505, was already being studied in myelofibrosis, a rare blood and bone marrow cancer where abnormal collagen and fibrosis are central features and has been shown to be well tolerated in early-phase clinical trials, meaning that its safety is being established, which can accelerate translation to ILC clinical trials. Since PXS-5505 blocks LOX enzymes involved in collagen remodeling, we asked whether the same drug could also interfere with the collagen-rich environment that ILC cells rely on.

Question: This paper talks quite a bit about genes, proteins, and structures that are around the cancerous cells. Does the drug in question ever directly attack the cancer cell itself? If your answer contains the words “the ILC matrisome” and/or the ECM, can you explain these terms and why they are important?

Dr. Sflomos’ Answer: PXS-5505 targets a biological process that cancer cells use to shape their surroundings. The ECM, or extracellular matrix, is the network of proteins and structural molecules around cells. A simple way to think about it is as the “scaffolding” or “supporting mesh” that surrounds cells in a tissue. This matrix is not passive. It can send signals to cells and influence whether they grow, move, survive, or respond to treatment. The matrisome refers to the full collection of genes and proteins that make up or regulate this extracellular matrix. So, when we talk about the “ILC matrisome,” we mean the particular set of matrix-related molecules that appear to be important in invasive lobular breast cancer. 

In this study, the drug affects ILC indirectly. By blocking LOX enzymes, it changes the collagen structure around the lobular cancer cells. This disrupts the signals that ILC cells receive from their environment. In other words, the drug may not “attack” the cancer cell in the traditional sense, but it interferes with a support system that the cancer cells appear to need.

Question: What does this study uncover related to collagen and its relation to ILC tumor cells?

Dr. Sflomos’ Answer: Collagen is one of the main structural proteins in the body and the most abundant protein in animals. The study shows that collagen is not just a background structure around ILC cells. It appears to be an active part of the lobular disease biology. In ILC, the cancer cells seem to live within and interact with a collagen-rich environment. LOX enzymes help cross-link collagen fibers and can create conditions that help cancer cells grow and spread.

The study suggests that ILC cells can depend on this collagen-rich scaffold. When LOX activity is blocked, the collagen structure changes. As a result, the cancer cells lose some of the growth and survival signals they receive from their surroundings. This helps explain why targeting collagen remodeling could be a promising strategy in ILC.

Question: Is this work considered translational research? If yes, can you discuss some of the key components of the study that demonstrate that this study may be ready to move to the clinic — in other words, into human subjects?

Dr. Sflomos’ Answer: Yes, this is a strong example of translational cancer research. Translational research takes discoveries from the laboratory and moves them toward clinical use for patients. Several parts of this study support its translational potential. First, the use of more realistic ILC models that better reflect how lobular breast cancer grows in patients. Second, the drug tested, PXS-5505, is not just a theoretical compound; it is already being evaluated in early-phase clinical trials for myelofibrosis, where it has shown evidence of safety, tolerability, and biological activity. That makes future testing in breast cancer more realistic than if the drug were completely new. Third, the study identified potential biomarkers — measurable changes in collagen structure and gene activity — that could help researchers determine whether the drug is working in patients. This is especially important for designing early clinical trials, such as “window-of-opportunity” studies in which patients receive one or more new compounds between their cancer diagnosis and standard treatment (mainly surgery). However, it is important to be cautious. This work does not yet prove that PXS-5505 will benefit patients with ILC. It provides a strong rationale for carefully designed clinical studies to test that possibility.

Question: What are you most excited about in the next steps of this work?

Dr. Sflomos’ Answer: What excites me most is that this work points to a new weakness in lobular breast cancer that comes from its own unique and distinct biology compared to  non-lobular breast carcinomas. Since ILC was first described in 1941 by pathologists Foote and Stewart, it has generally been treated in the same way as other types of breast cancer. Our study suggests that ILC may depend on specific features of its surrounding tissue environment, especially collagen remodeling and the extracellular matrix, and that these dependencies could potentially be targeted therapeutically.

The next important step would be to test whether these findings can be translated into patients. A carefully designed clinical study could examine whether PXS-5505 changes collagen structure and tumor biology in people with ILC. It will also be important to identify which patients are most likely to benefit and whether this approach should be combined with standard treatments such as radiotherapies, endocrine therapy and immunotherapies.

The broader excitement is that this could open the door to a more biology-driven approach to ILC treatment — one that not only targets the cancer cell itself but also the specific environment that helps lobular cancer cells survive and progress.

References

https://aacrjournals.org/cancerres/article/86/10/2487/784888/LOX-Inhibition-Disrupts-a-Collagen-Integrin-MYC

https://link.springer.com/article/10.15252/emmm.202013180

https://link.springer.com/article/10.15252/emmm.202013807