Studying the Tumor Microenvironment of Hepatocellular Carcinoma

Amaia Lujambio, MD

Hepatocellular carcinoma (HCC) is a unique disease that not only presents differently in each patient, but also has a wide range of genetic mutations, explained Amaia Lujambio Goizueta, PhD, during a presentation at the 2021 International Liver Cancer Association Conference.

Even with the plethora of studies that have occurred in the field, unanswered questions remain and until certain questions are answered, HCC remains a challenge for oncologists to treat.

“We get new question every time we get new answers, so it's a never-ending process,” Lujambio, an associate professor of Oncological Sciences and Medicine in Liver Disease at the Icahn School of medicine at Mount Sinai, told Targeted Oncology™.

Building upon research around the molecular makeup of HCC, resistance mechanisms, and individualized options for treatment is ongoing in the field.

In an interview, Lujambio, discussed the diversity of genomic alterations in HCC and advanced in molecular testing that could shape future understanding of the disease.

TARGETED ONCOLOGY™: Can you explain the diverse molecular makeup of HCC?

So, every tumor is very diverse and every tumor type, but HCC, it's in particular, very diverse if we compare it to other tumor types. That means that tumors from different patients have very different mutations, and very different combinations of mutations. The gene that is most frequently mutated is the promoter of a telomerase of TERT, which confers the cancer cells with unlimited replication potential. There are also other genes such as p53, and beta catenin, that are also frequently mutated. However, the way these genes are mutated, they are not mutated together, they are mutated in different patients. So, that makes it more difficult to treat, because right now, there are not selective therapies for HCC patients. All the patients receive the same treatment. There are different therapies, but there is not a way of selecting the best therapy for each patient.

The hope for the future is that we can identify which mutations confer sensitivity to a specific therapy, so that we compare each patient with each a specific therapy. And in addition to this great genetic heterogeneity that is present among the different HCC patients, something to consider is that HCC in most of the cases appears in a liver that has been damaged, and the way of damaging the liver can also be very diverse. So, that adds an additional layer of complexity to the problem because you can have 2 patients with maybe the same driver mutation, but 1 patient has a liver with hepatitis B and the other one has a liver with a non-alcoholic state of hepatitis. That is going to completely change how that patient responds to therapy. For an oncologist and their patients, this can be a very challenging disease.

From a pathologist’s perspective, how would you advise oncologists on how to order genetic testing for HCC?

I think the main idea in the whole liver cancer field is that we need to keep studying liver tumors as much as possible. One challenge with that is that patients with liver cancer, they are very sick, not only because they have cancer, but also because their liver is damaged. So, they receive a treatment, and in many cases, is not recommended that the treating physician takes a sample from the tumor so that it can be studied. So, it's tough to ask a patient that is in very bad shape to undergo a procedure that can represent a risk for their health. So ideally, we would like to study, like the genetic makeup of the tumors of every patient and how they respond to each therapy that that patient is receiving, so that we have a more complete picture. This is all very challenging because of this fact.

There are other strategies that people are developing such as liquid biopsies, which basically means that you can detect the mutations from the tumor cells in the blood of the patient. And it may offer a similar level of information in terms of choosing the best therapy. So, whenever possible, we need to study as much as we can, every single aspect of the tumors. And if that's not possible, then implementing liquid biopsies could be a great strategy as well. Then we need to combine basic and translational research, so that we come up with the best therapy options for each genetic alteration.

What are the unanswered questions in this field right now?

We get new question every time we get new answers, so it's a never-ending process. But a, 1 of the biggest questions is which therapy is appropriate for each patient? And even if there are challenges in trying to address that question, there are also advances. There was an interesting study this year, where they found out that those patients that have a liver associated with nonalcoholic steatohepatitis, those patients in general respond worse to monotherapy. So that was a great discovery this year, but then that begs the question of, what therapy should we use with those patients and definitely combining research with a mouse model with knowledge from patient samples again will be critical to address this question.

Another interesting question is the heterogeneity among different patients, which is critical, but also a liver tumor within a single patient, they can also be very diverse. So not all the tumor cells within a tumor are identical. That means that you may have some cells that respond to therapy, but or others that don't, and the tumor will develop resistance to the therapy. So that's going to be another important challenge and a question to address in the next few years. Luckily, now we have technologies based on single-cell analysis of either DNA or mRNA, or proteins that are going to enable us to study this a little bit more.

Another important research question in HCC is how tumor cells escape the immune system. Can you discuss your research in this area?

The immune system in is going to always try to attack the tumor, but the tumor is very smart and basically has different ways of hiding from the immune system. And there are many different ways of hiding. So, we have found that tumors that present genetic alteration, which is overexpression of NOTCH, which can be an oncogene in hepatocellular carcinoma, they are very good at hiding from the immune system. That makes the tumors with a NOTCH overexpression be resistant to immunotherapy. I keep coming and repeating the word in immunotherapy because this is one of the therapies that is most promising right now in HCC. So, we are trying to decipher the mechanism by which NOTCH on oncogene is inducing immune escape. So, we have found that there are the tumors that have a lower ability to attract T cells, which are cells of the immune system that can recognize specifically the tumor cells and a basically kill them. There is a definitely a defect in the ability of those cells to recreate the immune T cells, but also we are seeing that those T cells that actually managed to get to the tumor, they are not able to kill the tumor cells.

If we are successful with our research, which is conducted mainly in models, and we find a similar mechanism in HCC patients, then that the therapies that we are testing in models could be a used in patients. That's the ultimate goal.