2026.10.10 | GP | Biotech | Li-Fraumeni Syndrome Therapies KOL

Associated:

PMVP

MYGN

TEM

NTRA

GRAL

GH

Viewpoint:

Academic KOL - Physician Scientist

Moderator: Aayushi Purohit (AP)

Thai Ho (TH), Director of Precision Medicine and Associate Professor in the Division of Hematology and Oncology - Medical University of South Carolina

SUMMARY

Overview

Li-Fraumeni syndrome is an autosomal dominant cancer-predisposition disorder caused by germline TP53 alterations. It creates exceptionally high lifetime cancer risk, including early breast cancer, sarcomas, central nervous system tumors, and adrenocortical cancer. Diagnosis relies on personal and family cancer patterns, broad genetic testing, and confirmation that blood-based findings are not age- or treatment-related clonal hematopoiesis.

The expert favors intensive standardized surveillance for all confirmed carriers because current risk models are not sufficiently reliable for reducing screening. Treatment generally seeks to limit radiation and genotoxic chemotherapy due to secondary malignancy risks.

Key Insights

Variant biology materially affects disease onset. Dominant-negative missense variants are associated with earlier and more pediatric cancers, while loss-of-function variants generally present later. Blood-detected TP53 variants should be confirmed using cultured skin fibroblasts because 20%–40% may reflect clonal hematopoiesis rather than inherited disease. Annual whole-body and brain MRI remain central to surveillance. Liquid biopsy may detect disease earlier but should complement, not replace, imaging. The largest unmet need is chemoprevention. Metformin is the leading practical candidate because of its established safety, low cost, and biological rationale. Mutant-p53 reactivators may require combination therapy, while ATR inhibition appears more promising than earlier WEE1 inhibitors because of lower marrow toxicity.

Clinical Data

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Area

Findings

Inheritance

Each child of a carrier has a 50% probability of inheriting the variant.

Cancer risk

Lifetime risk approaches 90%–100% in women and 70%–75% in men; overall risk is about 24 times that of the general population.

Multiple cancers

40%–50% develop two cancers; 15%–20% develop at least three.

Surveillance benefit

Five-year survival was 89% with surveillance versus 60% without it in an observational study.

Whole-body MRI

Specificity was 95%, negative predictive value 97%, and sensitivity 43%.

Radiation risk

Secondary cancers may arise within 2–10 years; retrospective estimates were 30%–40%.

Liquid biopsy

Positive predictive value was 68%, negative predictive value 97%, with detection 7–10 months before MRI in some cases.

Metformin trial

Participants aged over 16 receive metformin plus surveillance or surveillance alone for five years. A 30%–40% risk reduction was viewed as clinically meaningful.

Competitive and Therapeutic Landscape

Approach

Positioning

Key limitations

MRI surveillance

Current standard with demonstrated survival benefit

False positives and limited sensitivity

Metformin

Most deployable prevention candidate

Efficacy remains unproven

Y220C p53 reactivator

Targeted option for a rare mutation; 20% overall response and 30% in KRAS-wild-type disease

Anemia, frequent dose modification, and likely need for combinations

ATR inhibitors

Promising synthetic-lethal strategy

Early clinical development

WEE1 inhibitors

Mechanistically relevant

Limited single-agent activity and marrow toxicity

Newer PARP inhibitors

Reduced trapping may improve tolerability

Secondary malignancy and myelosuppression concerns remain

Molecular degraders

Potential direct targeting of mutant p53

Primarily preclinical

AP: Hello, everyone. Good afternoon. Welcome to Guidepoint's teleconference. Today we are joined by Dr. Thai Ho

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who will be talking to us about Li-Fraumeni Syndrome and its overview. My name is Aayushi and I'll be moderating today's teleconference. If you have any questions for our advisor, please feel free to email us at ask@guidepoint.com. And just as a reminder, we'll be talking about publicly available information only. Dr. Ho, thank you so much for joining us here today. So could you start off by providing a brief introduction to your professional background and your research interest?

TH: I'm a physician scientist by training. I have an MD and a PhD. I lead the precision medicine initiative as well as run a hereditary clinic for patients affected by germline syndrome. I treat patients in both the hereditary syndrome setting as well as the sporadic setting. And then I also run an NIH-funded translational lab focusing on novel synthetic lethal screens for various targets.

AP: Perfect. So to start with, if you could give us an overview about LFS, its etiology and pathophysiology of LFS.

TH: Li-Fraumeni syndrome is what they call autosomal dominant syndrome. That means if patients carry the gene, then 1 in 2 offspring will be affected. It's a highly prevalent disease with regards to once you diagnose a family, there may be other family members who are involved. The key mutation is in the TP53, which is a tumor suppressor gene on chromosome 17 and the function for this gene is maintaining genomic stability. When you look at the variations in terms of frequency, it's between 1 in 3,000 to 1 in 10,000, and the cumulative lifetime cancer risk approaches 90% to 100% in female carriers driven primarily by premenopausal breast cancers and then reaches about 70% to 75% in male carriers. These patients have a 24-fold higher risk of cancer compared to the general population.

AP: Got it. Now, before we start to talk about LFS, how many patients do you have under your care or do you have under your clinic who are either a patient of LFS or who could be LFS patient potentially?

TH: Our clinic probably has about 40 to 50, 10 to 15 are personally on my care and I am the primary driver of the surveillance imaging.

AP: Got it. Now, which personal or family cancer patterns should prompt testing for a germline TP53 variant?

TH: There are sort of 3 criterion that we use. 1 is the familial criterion where you have a patient with the core tumor, so this includes sarcoma, breast cancer, CNS tumor, adrenal tumor. These are patients diagnosed below the age of 46 and at least 1 first or second person relative with the core tumor below the age of 56. Another criterion is somebody who has presented with multiple tumors, including the 2 core tumors, which are the sarcoma, breast, CNS, adrenocortical tumors with 1 of them below the age of 46. Rare tumors also, this is sort of the criterion 3 where they have the adrenocortical carcinoma, choroid plexus carcinoma, anaplastic embryonal rhabdomyosarcoma, irrespective of family history, and then any early age of breast cancer below the age of 31, irrespective of family history. For the pediatric setting, these also encompass some of the low hypodiploid acute lymphoblastic leukemias, medulloblastomas, osteosarcomas, or the history of a development of a secondary primary malignancy within a prior radiation field.

AP: Got it. And then how often is Li-Fraumeni Syndrome identified? Only after a patient develops multiple primary cancer, how is it actually diagnosed?

TH: So typically these patients, 40% to 50% will develop 2 cancers, 15% to 20% develop 3 or more cancers. The patients that may be missed in earlier testing may be in earlier eras where they undergone only a targeted single gene testing. Probably the most common is they had a history of breast cancer. They only got tested for BRCA testing and they didn't have any pan-cancer panels. So that leaves their TP53 mutation status unrecognized.

AP: Got it. And then if you could also talk to us about how do you distinguish between classic LFS from broader

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heritable TP53-related cancer syndromes.

TH: So the classic LFS are patients carrying a germline TP53 variant who meet sort of the classic clinical diagnostic criteria. So these include things like through the addition of the Chompret criteria, early breast cancer, rare pathognomonic tumors, multiple core primaries. There can be some variant carriers, so these fall into the attenuated LFS, where they present with the adult onset malignancy or have incomplete familial penetrance. These usually don't meet classic or Chompret definitions. And then for incidental TP53 carriers, these are patients who carry pathogenic germline variants following broad population sequencing, commercial testing panels, but they don't have a personal or family history.

AP: Got it. And then how much does a type of or the location of the TP53 variant affect the cancer risk in terms of the age of onset and even the tumor spectrum?

TH: So depending on the location of the mutation, a lot of the missense variants located within the core DNA binding domain, these often exert a dominant negative effect, which means that the presence of these alterations actually interfere with the normal function. So normally we have 2 copies of TP53, and if you have 1 of these gain-of-function or core DNA binding mutations, these are the R175, G245, R248, R249, R273, R282, these can interfere with the copy of the TP53 gene. These patients have dominant negative alterations, have an earlier age of cancer diagnosis, usually between 15 to 20 years, and they have a higher incidence of adrenocortical carcinomas, choroid plexus carcinomas, medulloblastomas, and osteosarcomas. The other group is the null allele. So these are patients who have these nonsense mutations, frameshift alterations, splice disruptions, exon deletions, and these cause haploinsufficiency. So you still have a competent allele that's still working, but it's at a reduced operational abundance. So that means another stochastic event has to occur, and this shuts down the remaining allele. So these carriers have a median age of onset a little bit older, between 28 to 35 years. They have a lower burden of pediatric neoplasms and an elevated lifetime risk of premenopausal breast cancers, soft tissue sarcomas, and adult gastrointestinal carcinomas. So you essentially have sort of a delay in when the cancers have an onset, whether they have the core DNA-binding mutation versus a null where 1 copy is lost.

AP: Got it. And how do the variants of uncertain significance would be handled when the patients have a strong history or even have the TP53 variant effect that suggests it is LFS?

TH: So for patients affected by these VUSs and TP53, it's always ideal to check in with the provider who ordered the testing or even contact the lab that performed the testing to ask about the current classification of the variant. For some of these companies, they do have an integration to electronic medical records, so they'll update things or notify providers when there's new classification changes. There isn't a consistent policy who is responsible for the updates, whether it be the electronic medical record vendor, healthcare provider that ordered the test, but once they develop a cancer, I think that can set them on the path of the routine surveillance screening.

AP: Got it. Now, how do you distinguish a true germline TP53 from clonal hematopoiesis mosaicism and even tumor- derived finding? If you could just give us a brief overview what these are different variants and how do they differ?

TH: Clonal hematopoiesis of indeterminate potential, or CHIP, is an age-associated expansion of somatic mutations within the stem cell populations of the bone marrow. Because TP53 is one of the common 5 genes frequently mutated in CHIP, these age-related expansions, prior therapies can expand these hematopoietic clones and can lead to a false positive, and up to 20% to 40% of pathogenic TP53 variants on the commercial multi-gene blood panels may represent CHIP rather than true germline inheritance. A diagnostic standard actually requires using a punch skin biopsy followed by DNA sequencing of cultured dermal fibroblasts. This basically suggests that this is now present in the germline, so this is better than saliva testing, and the absence of the variant in cultured skin fibroblasts confirms CHIP. It also avoids inappropriate LFS diagnosis, any kind of unnecessary cascade testing, and lifelong cancer

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screening. Vice versa, if you have the variant confirmed with the cultured fibroblasts, it confirms either constitutional mosaicism or true germline inheritance, and this allows you to activate the need for standardized surveillance protocols.

AP: And when should children and other relatives of a TP53-positive patient be offered cascade testing?

TH: I think anybody who is diagnosed with classic LFS, these are patients with the germline TP53 variant who meet classical clinical diagnostic criteria originally from 1988 or the Chompret associated LFS where they have the revised criteria where they have early breast cancer, rare pathognomonic tumors or multiple core primaries because these children can be at a higher risk of pediatric malignancies as well.

AP: And can the current risk models reliably personalize surveillance or should most TP53 carriers follow the same intensive protocol?

TH: So there is active research in this area. I believe that TP53 carriers should follow the same intensive protocol for now. There are prediction packages such as LFS-PRO that calculates the carrier probabilities and cancer-specific penetrance. This was developed in 2017. So it incorporates things like family cancer histories, organ-specific competing risk, age penetrance schedules. And this was validated in a paper from MD Anderson in May 2026, where it does have a higher sensitivity compared with Chompret criteria. The sensitivity was 81% versus 33%. Specificity was also improved 88% versus 65% with an improved negative predictive value, so 0.53 versus 0.14. However, in general, the international guidelines from Europe, the UK, and AACR still believe that the risk prediction algorithms can't be used to de-escalate clinical surveillance. And because the lifetime penetrance remains high across all the various TPC variants, and there may be variations in biology, it's still best to follow standardized high-intensity surveillance protocols to identify earlier stage tumors where they are more treatable.

AP: Got it. Now, if you could talk to us about what does the current standard surveillance protocol look like for children and adults with LFS?

TH: So this is based on the revised criteria from AACR put out in 2025. This is based on the Toronto Protocol. So the starting age for children starts at 18 in terms of general assessments, screening for sarcoma, CNS tumors, leukemias, adrenal tumors, and skin cancers. These occur every 3 to 4 months clinically. And then they also try to get things like whole-body brain MRI, initial brain MRIs, blood chemistries, dermatologic screening at a minimum of every year. Once patients start at age 18, they are taught about self-exams and then they have breast awareness discussions at age 18.

AP: And then does that differ for adults?

TH: So for adults, you now have a skewing of tumors away from the pediatric tumors. So now you're getting into breast MRIs and mammograms after the age of 20. This is done annually. In terms of screening for sarcomas, this is done every year with whole-body MRIs. For CNS tumors, this is again done with the brain MRI every year. For the skin cancers, annual dermatologic screening, and now you have abdominal and pelvic ultrasounds for the adrenal tumors. This can be performed every 6 months with and without the blood biochemistry. Prostate cancer screening starts at age 35 annually, and then for the GI cancers, you have a colonoscopy and endoscopy every 2 to 5 years starting at age 25.

AP: Understood. Now, how do you balance earlier cancer detection against false positives?

TH: So as a standalone surveillance tool, whole-body MRI demonstrating a pan-cohort specificity of 95%, negative predictive value of 97% with a sensitivity of 43%. In terms of the anxiety or scan anxiety, they did an observational study. This was published in Lancet Oncology in September 2016 in which patients either agreed to surveillance or

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didn't agree to surveillance and the patients who agreed to surveillance, the 5-year overall survival was 89% versus the patients who declined surveillance, their overall survival at 5 years was 60%. So this is sort of the importance of these annual surveillances. And people have done case control studies in various countries and they find that although anxiety may be the highest prior to the scans, it goes back to baseline after 2 weeks. And patients are very... they like the idea of active surveillance because the risk to their disease progression is much higher than having some of the issues with anxiety. So it actually gets better with scheduled scans.

AP: And then now once there is a patient who is positively diagnosed with LFS, how does that change the treatment when the patient develops cancer?

TH: So depending on which type of cancer they develop, it changes their treatment outcomes. So female breast cancer is the most frequent cancer in LFS. It's an 85% lifetime risk. So when they looked at the patients who had a unilateral surgery versus a bilateral surgery. Half the patients who did not have a contralateral surgery within a year of their breast cancer diagnosis developed contralateral breast cancer. In that study, about 8% or 18% of patients underwent bilateral risk-reducing mastectomy after their diagnosis, and the median age of the risk-reducing mastectomy was 39 years, which is somewhat suboptimal given that the average age of breast cancer diagnosis is 32 years old. So waiting until 39 may be beyond the level where you might be able to reduce the risk reduction. So this finding at least underscores the importance of discussions of risk reduction of bilateral mastectomy in their 20s and 30s. This is very different from the BRCA mutations where a bilateral oophorectomy is not standard recommendations for patients with LFS. Once patients are diagnosed with treatment, we try to avoid radiation when possible. So when patients have breast cancer, we tend to avoid breast conserving surgery because it mandates whole breast adjuvant radiation. So it's preferable to do total mastectomy to minimize the radiation. Also, in terms of what's known about ionizing radiation, it causes double-strand DNA breaks. So these patients with LFS without adequate repair mechanisms will accumulate DNA mutation and chromosomal rearrangement. So it's known that they will have secondary infield cancers that develop within 2 to 10 years following radiation. So these are 30% to 40% in retrospective studies where they have an infield cancer related to osteosarcoma, pleomorphic sarcoma, or soft tissue sarcoma after radiation. So we try to avoid radiation if possible. If radiation has to be deployed, then we try to refer them to sites that have proton therapy where this may minimize the lateral side scatter and minimal exit doses compared to conventional radiation. When it comes to chemotherapy options, we try to avoid things like alkylating agents such as cyclophosphamide, ifosfamide, or topoisomerase inhibitors such as etoposide, doxorubicin, because these can lead to secondary myelodysplastic syndromes, leukemias. So we try to see if we can slot in immunotherapies for these patients where they would not be exposed to these potential secondary risks of myelodysplastic syndromes or leukemias.

AP: And as you talked to us about radiation, so when is radiation or genotoxic chemotherapy clinically absolutely necessary? And then how should the risk of secondary malignancy be managed?

TH: So these are primarily in pediatric patients. So the development of these secondary cancers occur 2 to 10 years following radiation. If a patient has to get irradiation, then using the MRIs post-radiation to surveil for infield cancers is useful. And then for patients who have to receive alkylating agents or topoisomerase inhibitors, we monitor for the development of myelodysplastic syndrome leukemias through routine CBCs looking for evidence of any kind of unusual morphologies, blast cells.

AP: Got it. Now, before we move on to some of the upcoming pipeline therapies, what is the greatest remaining unmet need in LFS?

TH: I think this would be chemoprevention strategies. So, we know that these patients have a high pretest prevalence of disease progression, surveillance, you're kind of waiting for something to occur. I think that for these patients, there's potential for chemoprevention down the road. We already use drugs such as Everolimus in patients affected

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by tuberous sclerosis. We use drugs like Belzutifan which targets hypoxia-induced pathways in patients affected by von Hippel-Lindau syndrome. So, these are both similar autosomal dominant familial syndromes where they have multi-organ cancers that can arise, and these drugs help reduce the morbidity associated with these cancers.

AP: Now, moving on to talk about some of the upcoming pipeline therapies, what biological evidence does it support using metformin as a cancer prevention strategy in LFS, specifically the MILI trial that they have done?

TH: So, part of this stems back to a Journal of Clinical Investigation paper published in January 2017 where they made an LFS mouse model. So, what they did is they knocked out both TP53 genes, and this leads to increased mitochondrial stress associated with the development of thymic lymphomas. And interestingly, they noticed that metformin reduced mitochondrial stress and improved cancer-free survival. If you look across other species, you know, humans, we have 2 copies, but elephants will actually have 20 copies. So, elephants actually rarely have any cancer. Despite being a much larger animal, higher cell mass, potentially higher metabolism, their risk of cancer is 5 times lower than humans, and their life expectancies in their 60s and 70s. So, this is sort of an interesting observation between different species. Now, with mice, at least they have 2 copies, so that kind of mirrors what we see in humans. However, with these different studies, there's studies going on in the UK, the NIH, and Germany; so these are all variants of the metformin in adults with Li-Fraumeni syndrome, or the MILI trial, where they're randomizing patients over the age of 16 to either oral metformin plus annual surveillance or annual surveillance alone. And the primary endpoint is to look at the cancer-free survival over 5 years. So number 1, it will ask the question, what's the annual penetrance of detection by annual MRI in the control arm? And in the experimental arm, does adding a generic drug like metformin reduce mitochondrial stress to the level that actually will reduce the risk of cancer? So the ideal improvement would be at least a 30% to 40% risk reduction. Since the side effect profile of metformin is certainly better than conventional adjuvant chemotherapies and it's generic, so it's something that's cheap that can be deployed. Most of the side effects of metformin are transient, so things like the diarrhea, gastric upset, nausea, these often get better with adjusting the dose of metformin.

AP: And then what results would metformin studies need to show, specifically the primary endpoint that they have shown to become a part of routine management?

TH: I think at least 30% to 40% risk reduction. This would put it into the same level of evidence where we've used for other chemoprevention studies like the selective estrogen receptor modulators such as tamoxifen or raloxifene for breast cancer, finasteride to lower the risk of prostate cancer, and COX-2 inhibitors to reduce the risk of colon cancer or polyps.

AP: And then which patients are most likely to benefit from metformin? Could the TP53 variant type or metabolic profile predict response?

TH: So I think the higher the pretest probability of developing cancer are the ones that are going to show the greatest benefit. So if metformin can truly reduce mitochondrial stress long term, it would really benefit the patients with these missense variants where they have an earlier diagnosis of cancer and a higher incidence of cancer. So these are the patients with missense variants located in the core binding domains. Essentially, these patients have a median age of first cancer diagnosis of 15 to 20 years with high incidences of kind of rare cancers, such as these adrenal cortical carcinomas, choroid plexus carcinomas, medulloblastomas, and osteosarcomas.

AP: Got it. Now, what long-term safety and adherence concerns would arise when prescribing metformin to otherwise healthy TP53 carriers?

TH: I think given widespread use in diabetes, we find that these gastrointestinal side effects like cramping and diarrhea are self-limited. I think that these patients will be followed out over 5 years to see if there's any other unusual

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side effects or other unusual cancers or shift in diagnosis of cancers as a result of metformin, but at least it's a drug that is FDA approved. It's been on the market for years and it's been used for patients with diabetes for many, many years.

AP: Got it. Now, how could circulating tumor DNA detect an emerging cancer before it becomes visible on the whole- body MRI?

TH: So I think this is something that, because it's a high pretest probability, it increases the likelihood of detecting DNA. One thing that they do have to be able to identify is difference between clonal hematopoiesis versus a normal variant or the germline expression. But at least in a cancer discovery paper in 2024 with serial plasma DNA profiling, they identified that this could identify patients when you look at both fragmentation with target methylation that could identify some preclinical malignancies. So it detected emerging cancers with a positive predictive value of about 68%, the negative predictive value of 97%, and the lead time between the detection on the DNA to when you saw a whole- body MRI could be anywhere from 7 to 10 months. However, I think that you have to make sure that this is something that is done with the MRI instead of in lieu of the MRI because it's a population that's already undergoing regular imaging. So liquid biopsy in theory should have a very high specificity to minimize false positives, any unnecessary biopsies and invasive exploratory procedures and it must demonstrate a sensitivity that's high, greater than 70% to 80%, particularly for the rare cancers like soft tissue sarcomas, osteosarcomas, adrenocortical carcinomas, because we have surveillance already in place for things like breast cancer, and you also need some degree of tissue of origin accuracy as well. Ideally, you know, you can look at case control studies or observational studies. But you eventually have to do prospective randomized studies to 1, demonstrate that patients live longer as a result of early detection, because when you have early detection with circulating tumor DNA, it doesn't always tell you what kind of tumor it is, it doesn't tell you about location of tumor, and often these tumors are cured by surgery, not by radiation, and you have to be able to see it on MRI for you to have an opportunity to resect the tumor.

AP: And then how do you see circulating tumor DNA fitting and MRI both fitting together that could help the cancer become more visible? So do you think they could both have it at the same time?

TH: I would think it would be done at the same time so that it complements each other. It would not replace MRI because it doesn't show the location of disease, burden of disease, or imply curability. Plus, one of the challenges for these circulating DNA tests is that the shed rate will vary from tumor to tumor. So if you look at sort of the general oncology population, bladder tumors, colon cancers, breast cancers tend to shed better than kidney cancers or CNS tumors. You know, I think the liquid biopsy will vary in sensitivity and specificity by tumor type. And that's the challenge with these multi-cancer early detection assays is that you may have a generalized specificity and sensitivity, but it really should be distinguished tumor by tumor.

AP: Got it. Now, could mutant p53 reactivators address the underlying biology of LFS, or will their use remain limited to specific tumor variants?

TH: So I think as chemoprevention, you have to have long-term safety, it has to be tolerable. So these reactivators can refold the DNA domain to restore function. Some of these things may require some sort of vector. So some of the reactivators have been approved in Asia where it's specifically for head and neck cancer. So it's an adenovirus to restore TP53 function. You have to have improved delivery to tumor cells with the systemic administration. And then 2, some of these adenoviral vectors can cause inhibiting antibodies. You worry about integration effects. And then some of these tumors have such high levels of missense TP53 that it's not enough to reverse with just a drug alone.

AP: Got it. Now moving on to talk about 1 more therapy. How relevant is the PMV pharmaceuticals to LFS patients whose tumors carry the TP53 Y220C mutation?

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TH: So this was published in the New England Journal in February 2026. This is the phase 1 study. In general, across the patient population with oncology, 1% of cancers have the Y220C. It did exclude CNS tumors, so it means or suggests that it either doesn't cross the blood-brain barrier or they did not want CNS tumors in their initial phase 1. The response rate was 20% in the intent-to-treat population, which is primarily ovarian and breast. But if there was a KRAS variation, this led to some sort of intrinsic resistance or escape pathway. So if you look at KRAS wild type patients, 30% was the response rate. In looking at the side effect profile, it was about 14% grade 3 anemia, 65% dose modifications, 8% discontinuation. I think this would be potentially an option for patients with LFS, but my suspicion is that it has to be combined with something to really get a meaningful response.

AP: So what would be your expectations from this study moving forward and where do you see the benchmark in terms of efficacy and safety?

TH: I think that in terms of a long-term therapy, less than 5% discontinuation or less than 10% discontinuation, I think in the setting of metastatic disease, I think you can accept up to 20% treatment discontinuation rates. I think that these agents, when combined with other therapies, they would be compatible therapies that would cause peripheral neuropathy, some myelosuppression. I think that with the anemia, this would make it hard to combine with therapies that could cause some sort of concurrent anemia. And we know that current therapies that can be on the order of years include the drugs that we mentioned earlier, like Everolimus for tuberous sclerosis disease, belzutifan for von Hippel-Lindau.

AP: And then finally, over the next few years, which development most likely is to change biological management?

TH: So some of these synthetic lethal approaches look like they could be combined with the mutations. This is sort of the same mechanism by which PARP inhibitors were discovered for BRCA mutated tumors. So in terms of the synthetic lethality with TP53, these include Wee1 kinase and ATR inhibition. Sort of the first attempt was some of the early generation Wee1 kinase inhibitors that target the mitotic spindle. So 1 drug was Adatavisertinib. However, this led to a lot of bone marrow toxicity and single agent activity has been limited in phase 1 studies. With regards to ATR inhibitors, they seem to be a little bit more compatible with the less side effect profile on the bone marrow. These ATR inhibitors would basically allow the TP53 mutant tumor cells to divide without adequate DNA, and this leads to mitotic catastrophe and death, cell death. Some of the current generation include berzitinib, seracertinib looks promising in small cell lung cancer maintenance. PARP inhibitors are also currently under study, but I think the current generation of PARP inhibitors cause PARP trapping, so this increases the risk of myelodysplastic syndrome in patients who don't have TP53 mutations, and this may play into development of secondary malignancies and myelosuppression. So I would say that the newer generation of PARP inhibitors that have less PARP trapping, such as AstraZeneca, seem like they potentially could improve upon the activity in the setting of TP53. And then you have the molecular glues or degraders. These basically target the TP53 mutant, but these are primarily in the preclinical space.

AP: Perfect. Thank you so much, Dr. Ho, for the great data and insights that you shared with me. Thank you very much. Have a great day. Take care. Bye-bye.

TH: All right, thank you, bye-bye.

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