Sue Desmond-Hellmann
Assessments created by Dr. Kirk Ehmsen
Questions
- In her talk, Dr. Desmond-Hellmann says that ‘great drug development’ relies on a ‘deep understanding of basic science.’ Which of the following statements best represents the ‘basic science’ finding that ultimately led to the development of trastuzumab/Herceptin®?
- Which of the following statements most accurately describes a property of HER2 that is required for HER2 to be targeted by the monoclonal antibody trastuzumab/Herceptin®? [2001 paper, 2012 review]
- HER2 is a cytoplasmic receptor tyrosine kinase (RTK) that, when dimerized with other kinases, activates downstream cell survival and proliferation pathways.
- HER2 is a transmembrane RTK, with an extracellular domain that activates cell signaling pathways when dimerized with other RTKs.
- HER2 is a transmembrane RTK, with an intracellular domain that activates cell signaling pathways when dimerized with other RTKs.
- HER2 is an RTK that phosphorylates other kinases to activate downstream cell survival and proliferation pathways.
- None of the above
- A number of mechanisms may in fact contribute to the cancer cell-killing effects of trastuzumab/Herceptin®. Based on the 2012 review, which of the following statements IS NOT a proposed mechanism by which trastuzumab/Herceptin® may limit cancer cell proliferation? [2012 review]
- Herceptin® blocks dimerization of HER2 with other tyrosine kinases (such as HER3), which in turn reduces signaling through downstream kinase pathways involved in cell survival and proliferation.
- Herceptin® locks HER2 in a dimerized state with other tyrosine kinases (such as HER3), resulting in constitutive signaling through downstream kinase pathways that activate cell death by apoptosis.
- Herceptin® bound to HER2 leads to higher levels of the cell cycle kinase inhibitor p27, which leads to cell cycle arrest.
- Herceptin® interaction with HER2 blocks the formation of p95HER2, a truncated form of HER2 that no longer requires dimerization with other tyrosine kinases for activity.
- None of the above
- The 2001 New England Journal of Medicine paper uses Kaplan-Meier plots to track progression-free survival and overall survival of patients treated with chemotherapy alone versus patients treated with both Herceptin® and chemotherapy. [2001 paper]
Based on Figures 1 and 2 in the 2001 paper, which of the tables below best approximates the results at 1 year after patient enrollment in the study?
- In her talk, Dr. Desmond-Hellmann refers to Herceptin® as a ‘guided missile’ or ‘smart bullet’ for HER2-overexpressing breast cancers.
- a. What does Dr. Desmond-Hellmann mean by a ‘guided missile’ or ‘smart bullet’ for cancer?
- b. Why can’t Herceptin® be a ‘smart bullet’ for all types of cancer?
- In her talk, Dr. Desmond-Hellmann notes that FDA approval for Herceptin® in 1998 required concurrent approval for a diagnostic kit, HercepTest™.
- Based on Dr. Desmond-Hellmann’s talk, the 2001 paper, and the 2012 review, propose one means by which HercepTest™ might measure HER2 levels in a patient’s breast cancer biopsy.
- In the case of Herceptin®, why is a diagnostic for HER2 levels so important?
- Cancer treatment regimens often involve a series of therapies that may include chemotherapy and surgical removal of a localized cancer, when possible. In her talk, Dr. Desmond-Hellmann describes the long ‘development timeline’ (1991 – 2005) over which Herceptin® matured as an adjuvant therapy for patients with HER2-overexpressing breast cancer (06:43).In the 2001 paper, it was shown that for patients with metastatic HER2+ breast cancer, adjuvant trastuzumab with chemotherapy extends median survival by nearly 5 months. Later studies showed that for patients without discernable metastasis, adjuvant trastuzumab can double the “time to first distal recurrence” – a result that Dr. Desmond-Hellmann explains it earned a standing ovation when first reported at a medical meeting.
- What is an ‘adjuvant’ therapy, and in what way is Herceptin® an adjuvant therapy in the treatment regimens for metastatic and non-metastatic HER2+ breast cancers?
- What does Dr. Desmond-Hellmann mean by “time to first distant recurrence,” and what does this say about breast cancer metastasis in patients without discernable metastasis at the start of adjuvant trastuzumab therapy?
- Changes in proteins directly involved in the HER2 signaling pathway, or in proteins that function in alternative signaling pathways unrelated to HER2, can circumvent the breast tumor-killing effects of Herceptin®.In his 2012 review, Dr. Stern describes mechanisms by which HER2 over-expressing breast cancers may develop resistance to Herceptin®.
For each of the four proteins below, briefly explain:
- How the protein normally relates to the HER2 signaling pathway
- How changes in the protein can lead to Herceptin® resistance
HER2
PI3K
p27
IGF1R
- In his 2012 review, Dr. Stern describes a small molecule, lapatinib, which binds to the HER2 intracellular kinase domain. Both lapatinib, a small molecule, and Herceptin®, an antibody, inhibit downstream signaling by HER2 kinase.Compare and contrast small molecule drugs and antibody-based therapeutics:
- What advantage(s) might a small molecule therapeutic have relative to a monoclonal antibody therapeutic?
- What advantage(s) might a monoclonal antibody therapeutic have relative to a small molecule therapeutic?
- What major limitation(s) are likely to be faced by both small molecule- and monoclonal antibody-based cancer therapeutics?
- In her talk, Dr. Desmond-Hellmann discusses several issues that she believes are important to successfully progress a drug from an idea to the clinic. Name and briefly describe at least three things she suggests are critical for successful modern drug development.
Answers
- (b); The correct option most relevant to the development of trastuzumab was the report by Dennis Slamon and colleagues in 1987 that HER2 protein and/or HER2/ERBB2 gene copies occur at very high levels in 25% of breast cancers, and that patients with these breast cancer subtypes face lower median survival than their counterparts with normal levels of HER2 (2012 review, p. 1-1st and 2nd of ‘Focus on HER2’). Dr. Desmond-Hellmann explains that not only was this observation ‘scientifically compelling’, but it also ‘outlined an unmet need’ given that the 25% of individuals with HER2-overexpressing breast cancer were battling one of breast cancer’s most aggressive forms.
Video (03:26): “So let me start the Herceptin story with telling you about the scientific rationale in breast cancer. And this story really rests on some critical information about the role of oncogenes in driving cancer. And this specific oncogene, Human Epidermal Growth Factor Receptor 2, or HER2, is a gene that was thought to be associated with accelerating the growth of breast cancer. And the first clinical description of that growth acceleration came from Dennis Slamon and his colleagues as published in Science in 1987, and it is shown on this slide. If patients had too much HER2, either amplification or overexpression of HER2, as measured by FISH or immunohistochemistry that was associated with a shorter survival. So about 25% of women in this trial were HER2 positive, or over-expressing, and their median survival was only 3 years. Whereas the HER2 normal, about 75% of women who had a normal amount of HER2 lived a median of 6 to 7 years.”
2001 Research Paper, p. 783: “A growth factor receptor gene, human epidermal growth factor receptor (HER2), is amplified in 25 to 30 percent of breast cancers and in these cases the en- coded protein is present in abnormally high levels in the malignant cells.8,9 Women with breast cancers that overexpress HER2 have an aggressive form of the dis- ease with significantly shortened disease-free survival and overall survival. Laboratory studies indicate that amplification of HER2 has a direct role in the pathogenesis of these cancers, thereby providing investigators with an opportunity to target a therapeutic agent directly against the alteration.”
2012 Review Paper, p. 1: “However, only a handful of cancer biomarkers are clinically validated for treatment selection. One of these pharmacodiagnostic markers is the human epidermal growth factor receptor 2 (HER2, also called HER2/neu). HER2 is a receptor tyrosine kinase that regulates cell growth and differentiation signaling pathways and is significantly overexpressed (up to 100-fold) in ~20% of breast and gastric cancers when compared to normal tissues; HER2 expression is highly correlated with amplification of the human HER2- encoding gene ERBB2. ERBB2 was discovered initially as a gene that is highly amplified in a subset of breast cancers. Its role as a potent oncogene is supported by preclinical data that demonstrates that overexpression of the HER2 protein can transform cell lines in culture. Furthermore, clinical data demonstrate that ERBB2 amplification in breast cancer is associated with worse overall survival compared to patients whose tumors lack ERBB2 amplification. As a result of these observations, HER2 became a candidate of substantial interest for cancer biology and drug discovery.”
Note: Assessment goal: This question asks students to recognize what is meant by a ‘basic science’ finding and to identify the corresponding observation that was most relevant to fueling interest in trastuzumab development.
- (b) The extracellular domain of HER2 is required for Herceptin® to bind to HER2 and block its dimerization with other RTKs. Monoclonal antibodies (mAbs) have access only to surface features of a target cell, making any component of HER2 that is intracellular unavailable for recognition by a mAb.
Other choices either refer to an intracellular component of HER2 or incorrectly describe a property of HER2:
a – HER2 is not cytoplasmic;
c & d – no statement here refers to the HER2 feature essential for Heceptin® binding;2001 Research Paper, p. 783: “Several murine monoclonal antibodies against the extracellular domain of the HER2 protein were found to inhibit the proliferation of human cancer cells that overexpressed HER2, both in vitro and in vivo.”Also, refer to 2012 Review Paper, p. 2, Fig. 1
Note: Assessment goal: This question asks students to distinguish features of HER2 that are relevant to its role in breast cancer pathology from features of HER2 that are relevant to the way it can be specifically targeted by a therapeutic, Herceptin®.
- (b); Herceptin® is proposed to kill cancer cells by a number of possible mechanisms, most which relate to the inhibition of pathways that are otherwise promoted by HER2 activity. The pathways activated by HER2 kinase activity promote cell survival and proliferation and therefore it is inhibition of HER2 kinase activity that is important for Herceptin® function; HER2-activated pathways do not promote cell death, making (b) the mechanism that students will not find described in the 2012 Review Paper (p. 3 “Proposed trastuzumab mechanism of action”).
Note: Assessment goal: This question asks students to evaluate specific statements made about Herceptin® function, in relation to the role that the HER2 receptor plays in cancer cell survival and proliferation.
- (a); Figures 1A and 2A of the 2001 paper present data showing patient survival (%) as a function of time, labeled as ‘months after enrollment’. Reading the Survival (%) at 12 months after enrollment (approximately between the 10 and 15 marks on the x-axis) leads one to estimate the numbers presented in (a). Although each figure presents data for 3 panels (A-C; B & C separate out two types of chemotherapeutic lumped together in A), only data in panel A are needed to address patient survival with chemotherapy or chemotherapy + trastuzumab.Note: Assessment goal: This question asks students to analyze time-course data in one graphical format (the Kaplan-Meier plots), select data for one time point, and convert the data into a table representation.
- Sample answers:
(a) Dr. Desmond-Hellmann refers to therapies that can selectively seek out, identify and kill cancer cells as ‘guided missiles’ or ‘smart bullets’. Herceptin® is an example of a drug that recognizes a feature that is relatively unique to its intended target: high levels of HER2 on the cell surface. In this way, it might be called a ‘smart bullet’ or ‘guided missile.’Video (5:47): “And monoclonal antibodies, at the time that Herceptin was developed were thought to be kind of a pie in the sky dream for a smart bullet, a guided missile targeted to certain things like HER2 that were expressed on cancer cells.”
(b) Because Herceptin® utility relies on overexpression of HER2, Herceptin® utility is limited to those cancer types that overexpress HER2. Most cancer types do not overexpress HER2.
Note: Assessment goal: This question asks students to demonstrate an understanding of a conceptual term used by Dr. Desmond-Hellmann by first defining the term (a), and formulating a hypothesis/offering an explanation for why Herceptin® in this ‘smart bullet’ context cannot be a useful therapeutic for most other cancer types (b).
- Sample answers:
(a) Dr. Desmond-Hellmann and both suggested papers explain that HER2 levels can be quantitated at the level of gene copy number (fluorescence in situ hybridization/FISH) or at the level of cell surface protein levels (immunohistochemistry/IHC). Either one of these in principle could have been chosen as the basis for a HER2 diagnostic kit; it turns out that IHC is the approach used by HercepTest™.Video (4:05): “If patients had too much HER2, either amplification or overexpression of HER2, as measured by FISH or immunohistochemistry, that was associated with a shorter survival.”
2001 Research Paper, p. 784, Methods-Patients: “The level of expression of HER2 was determined by immunohistochemical analysis in a central laboratory.”2012 Review Paper, p. 1: “Current diagnostic tests commonly used for this purpose include immunohistochemistry to detect protein overexpression and in situ hybridization (fluorescence or chromogenic) to detect gene amplification.”
(b) A diagnostic for HER2 is critical for two reasons, both dependent on the fact that only HER2-overexpressing breast cancers may respond to Herceptin®:(1) Dr. Desmond-Hellmann explains that a diagnostic was critical to the success of Herceptin® trials because it acted as a predictive biomarker for patients that might respond to the therapy – therefore it allowed a smaller patient population to be used and a shorter study time in which to observe a meaningful result. Without having pre-identified the target patient population that might be responsive to HER2 targeting, the efficacy of Herceptin® would have been much more difficult to detect in clinical trials because most breast cancer patients in fact will not be helped by a drug that targets HER2.
Video (08:47): “Now the HER2 testing part of the Herceptin experience was a critical part of the lessons that I learned about product development when I worked on Herceptin. And what this slide shows you is a great example of why a diagnostic matters so much. It actually makes drug development cheaper and faster. And why is that? Well, this is a statistical representation of what might have been with the Herceptin study. In patients whose breast cancer has spread, metastatic breast cancer, or MBC, we knew before Herceptin median survival was 22 months. So 50% of patients had died by 22 months when you studied first line metastatic breast cancer. Let’s say that we expected the benefit of Herceptin to be to extend that survival from 22 months to 27 months, or a 5 month improvement in survival. Well if everyone in the study, or 100% of the patients, were HER2 positive, that 5 month difference would take about 1250 patients and 52 months duration of study. If we didn’t have the diagnostic test, and the truth was that only 25% of our study population had HER2 over expression, that study would have shown a 1.25 month difference, and taken 349 months, and 11,000 patients. We couldn’t have done that study. That study wasn’t possible. So the diagnostic allowed for a smaller patient group and a faster study.”
(2) Herceptin® is both expensive and can be associated with severe risks of cardiotoxicity, meaning that it should only be used in individuals who might benefit from its cancer-arresting properties (2001 paper, p. 783-,).
2001 Research Paper, p. 783, Abstract-Results: “The most important adverse event was cardiac dysfunction, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management.”
Also see: 2001 Research Paper, p. 788, Cardiotoxicity
Note: Assessment goal: This question asks students to apply an understanding of ways that HER2 levels can be examined to a diagnostic kit that was required for approval of Herceptin®. It also asks students to construct an argument for why a diagnostic has been critical to the development and use of this particular drug.
- Sample answer:
(a) Adjuvant therapy is a ‘treatment regimen after surgical removal of a localized cancer, with the goal of killing any clinically occult tumor cells that may have been left behind, thus increasing the chance of long-term disease-free survival’ (2012 review, p. 3-Table 1). Although somewhat difficult to detect in the text of the 2001 paper, chemotherapy or chemotherapy + trastuzumab are both adjuvant (post-operative) treatment regimens, meaning that the primary tumor has been surgically removed in these patients and it is the metastatic tumors that are monitored for progression-free survival. This means that in any case where trastuzumab is used, surgical resection has already aimed to remove the primary cancer mass.2001 Research Paper, p. 783, Abstract-Methods: “Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide with (143 women) or without trastuzumab (138 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women).”
(b) Dr. Desmond-Hellmann is referring to the time from surgical resection + chemotherapy + trastuzumab, until a metastatic node is identified in patients that underwent surgical resection of the primary breast cancer mass. The fact that metastases occur years later in many patients that appeared free of metastasis at the time of primary tumor resection, suggests that breast cancers metastasize early and adjuvant therapies (such as Herceptin®) that kill or limit the growth of these small metastases can significantly improve long-term patient survival.
In sum, post-operative therapies (adjuvant therapies) can be important to the effectiveness of a cancer treatment regimen for patients with both detectable and undetectable metastases.
Video (10:53): “Even better news came when we studied Herceptin, early on in the adjuvant setting. The time to first distant recurrence doubled. The time that women stayed in remission doubled when Herceptin was given just after surgery. And this news was so dramatic that it got a standing ovation when it was presented for the first time.”
- Sample answer:
(a) HER2 is the receptor tyrosine kinase (RTK) that is overexpressed on the surface of HER2+ breast cancers, and its extracellular domain can be targeted by the monoclonal antibody Herceptin®. Although it does not appear to bind a growth factor ligand on its own, it dimerizes with a number of other cell-surface receptor tyrosine kinases (in particular HER3) and when dimerized, its intracellular kinase domain phosphorylates a number of proteins that are involved in signaling cascades that ultimately result in cell survival and proliferation (DNA replication and progression through the cell cycle). Its overexpression drives the dimerization of receptor tyrosine kinases even in the absence of appropriate growth signals, which would normally be required for RTK dimerization and downstream signaling.(b) Some possibilities:
(1) The HER2 extracellular domain can be lost (HER2 truncation mutants) and the truncation mutant can still dimerize with other RTKs; in this case, Herceptin® has no way to bind HER2 and block its dimerization with other RTKs.
(2) Other ideas may come up; for example, HER2 expression could be down-regulated and a different signaling pathway could be activated to drive cell proliferation. PI3K(a) Phosphatidyl inositol-3 kinase is a cytoplasmic serine-threonine kinase that is phosphorylated downstream of HER2-HER3 dimerization. Phosphorylated PI3K is the active kinase form, and PI3K in turn phosphorylates other proteins that mediate the upregulation of survival and proliferation factors, or the downregulation of factors that promote apoptosis or cell cycle arrest.(b) Some possibilities: PI3K mutations that lead to constitutive activation overcome the need for the kinase to receive an upstream signal for activity. In this case, Herceptin® may block signaling from HER2 but to no avail, because the downstream signaling pathway is no longer dependent on upstream signals. p27
(a) p27 is an inhibitor of the cyclin-dependent kinase (CDK) that drives cell cycle progression (CDK regulates proteins involved in licensing of DNA replication). Signaling through HER2-HER3 dimerization typically down-regulates p27, meaning that blocking the HER2-dependent signaling cascade with Herceptin® can restore p27 levels sufficient to block cell cycle entry.
(b) Some possibilities: p27 can acquire mutations that keep its levels very low, even if the upstream signaling pathway on which its levels normally depend is blocked by Herceptin®. IGF1R
(a) Insulin-like growth factor receptor 1 is a cell-surface receptor that is upstream of cell survival and proliferation pathways that are independent of the HER2 signaling cascade. It is not affiliated with the HER2 signaling pathway.
(b) Some possibilities: If a cancer cell acquires mutations in alternative pathways that promote cell survival and proliferation (pathways not associated with the HER2 signaling pathway), Herceptin® will no longer forestall cancer progression because the cell proliferation signals are received from an alternative source – the cell is no longer dependent on the Herceptin®-inhibited pathway.
All the information above, plus explanations for these resistance mechanisms, is provided in the 2012 Review Paper, p. 4-6.
Note: Assessment goal: This question asks students to (1) demonstrate a basic understanding of a few proteins in the HER2 signaling pathway, and (2) to predict ways in which alterations in these proteins could circumvent the inhibitory properties of Herceptin®, leading to drug resistance.
- Sample answer:
(a) A small molecule is more likely to be able to reach intracellular targets, because it may be able to cross a cell membrane. Monoclonal antibodies are primarily restricted to extracellular targets. Other speculations might relate to the possibility that small molecules in some cases may be easier to deliver (e.g. administer orally in a pill) than antibodies, and may be easier and less costly to produce than antibodies.(b) A monoclonal antibody recognizes a series of surface features of a specific protein target, perhaps making it more specific for a target than a small molecule. Also, it is easier to concentrate antibodies at a target site than it is to concentrate small molecules, perhaps making some antibodies more potent therapeutics or reducing undesired side effects resulting from interaction with non-target proteins.
(c) In both cases, drug resistance is likely to be an inevitable problem in cancer therapeutics – arguing for combination strategies in the future.
No specific comparison between the two therapeutic types is presented in any of the resources here, but lapatinib is described in the 2012 Review Paper (p. 4, left column-Proposed lapatinib mechanism of action).
Note: Assessment goal: This question asks students to compare and contrast two major therapeutic types, small molecules and biologics (in this case, antibodies). They may rely on speculation and intuition here, drawing on prior experience.
- 10. Sample answer:
Dr. Desmond-Hellmann says that ‘great drug development’ stems from a number of matters, including:
(1) A deep understanding of the basic science that justifies the development of a drug for a particular use,(2) Optimization of a drug’s characteristics, including the delivery of the drug to its target and the effective lifetime over which it can carry out its desired effect following delivery (½-life),
(3) A determination of the right patient population in which the drug will be useful and effective (what she calls ‘personalized medicine’). In this latter matter, Dr. Desmond-Hellmann means that there should be some consideration of whether there are subsets of patients with certain characteristics in which a drug may be particularly useful; being aware of such a patient population can (a) help justify the development of the drug in the first place and (b) help in demonstrating the efficacy of the drug against its intended target, by focusing clinical trials on patients with characteristics expected to be relevant to the drug’s intended action.
She also notes more general features of drug development, suggesting that collaboration between colleagues and key decision makers (such as the FDA) can be important at all steps of the drug development process – from the conception of an idea in a lab (basic science) through to drug testing in the clinic (clinical trials), and finally throughout the drug approval process.
Note: Assessment goal: This question asks students to summarize the scope of challenges – from basic science to clinical studies – inherent to successful drug development.
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