Chapter 27 — Exercises

Peptides in Oncology: Hormone-Axis Blockade, Somatostatin Analogs, and Radioligand Therapy

No answers are provided here. Items marked † are challenge exercises — they require you to combine material from more than one chapter, or to reason about a case the chapter does not settle for you.

A note before you start: this chapter concerns cancer treatment. Some of these exercises ask you to write about how you would explain a therapy to a patient or a family member. Write those as though someone will actually read them, because the difference between an accurate explanation and a reassuring one is exactly what this book is trying to teach.

Part 1 — Recall and comprehension

A. In one sentence each, state what the following do: a GnRH agonist, a GnRH antagonist, a somatostatin analog, a PRRT construct.

B. Approximately when did each of the following enter routine clinical use: leuprolide, octreotide, degarelix, lutetium Lu 177 dotatate? Order them chronologically.

C. Define castrate level and explain why the term exists.

D. Name the four components of a PRRT construct and state what each one contributes.

E. What is carcinoid syndrome? List its principal features and state what causes them.

F. What does the suffix -relix tell you about a drug? What does -relin tell you? Give two examples of each from this chapter.

G. Explain what a chelator is and why a PRRT construct needs one.

H. State, in your own words, the difference between progression-free survival and overall survival.

I. Name the three "jobs" that §27.8 says every successful oncology peptide performs. Assign each drug in the §27.1 table to one of them.

J. What is a theranostic? What single component changes between the diagnostic and the therapeutic version of the same construct?

Part 2 — Applying the mechanism

K. Chapter 3 established that the hypothalamic-pituitary axis responds to the pattern of GnRH release. Draw a two-panel diagram: the first panel showing physiological pulsatile release and its downstream effect, the second showing continuous exposure and its downstream effect. Label the point at which desensitization begins.

L. A patient starting a GnRH agonist is told to expect "things might get a bit worse before they get better." Explain the biology behind that sentence in language a non-scientist could follow, in no more than 120 words.

M. † The chapter argues that the flare is "the intended mechanism observed during its first phase" rather than a side effect. Construct the strongest possible counterargument — that the flare should be classified as a side effect — and then say which position you find more useful and why. Note that "more useful" and "more correct" may not have the same answer.

N. Octreotide has eight residues where native somatostatin has fourteen or twenty-eight. List the three engineering strategies §27.4 describes and state, for each, which specific degradation route it closes.

O. † Suppose a company announces a new somatostatin analog that is linear rather than cyclic and contains only L-amino acids, but claims a long duration of action from a novel depot formulation. Using Chapter 4 and §27.4, describe what you would want to know before believing the claim, and identify the specific pharmacokinetic property the formulation would have to overcome.

P. Explain why the peptide in a PRRT construct does not need to produce a useful biological effect at its receptor. Then name one property it does need beyond binding.

Q. Beta particles from lutetium-177 travel roughly one to two millimeters in tissue. Explain both a therapeutic advantage and a toxicity consequence of that range.

R. † PSMA is expressed in salivary glands, kidney, and small intestine as well as on prostate cancer cells. Predict, before checking any source, what the characteristic adverse effects of PSMA radioligand therapy should be. Then look them up and note where your prediction was right, wrong, or incomplete — and what the misses tell you about reasoning from expression data alone.

Part 3 — Evidence and rating

S. Write a full four-line 📊 Evidence Rating for the claim "octreotide relieves the diarrhea of carcinoid syndrome." Then write one for "octreotide extends survival in neuroendocrine tumors." Explain why the two do not receive the same rating.

T. The chapter states that NETTER-1 enrolled patients with midgut, well-differentiated, somatostatin-receptor-positive tumors that had progressed on octreotide. For each of those four qualifiers, name a group of patients about whom the trial says nothing.

U. † A news article reports: "A radioactive peptide therapy has been shown to help patients with neuroendocrine cancer live longer." Identify every way in which that sentence goes beyond what NETTER-1 established. Then rewrite it as a headline that is both accurate and still readable by a general audience — and note what you had to give up.

V. Rule 3 of the rating system says never upgrade a rating with mechanism. Find one place in this chapter where the mechanism is exceptionally elegant and the evidence is nonetheless the only thing that earned the rating. Explain what an "upgrade with mechanism" would have looked like there.

W. The peptide-drug conjugate rating is issued at the level of a class rather than a molecule, and the chapter flags this as an exception to its own rule. Explain what is lost by rating a class, and describe a situation in which doing so would be actively misleading.

X. † Melphalan flufenamide received accelerated approval and was later withdrawn from the US market. Using only that fact pattern, write a short paragraph explaining to a patient why "it's FDA approved" is not a complete answer to "does it work?" — without implying that approval is meaningless.

Part 4 — Reading labels and dossiers

Y. Write the Field 7 entry (per the Dossier section) for lutetium Lu 177 dotatate from memory, then check it against the chapter. Which fields did you drop?

Z. Find the approved indication wording for one somatostatin analog from a primary regulatory source. Count the qualifying clauses. Then write a one-sentence version that a marketer would use, and identify precisely which clause each version drops.

AA. † Choose any two peptides from your own Evidence Dossier and complete Field 7 for both. Choose them so that one is an approved medicine and one is not. Then write two sentences on what the contrast between the two entries taught you that neither entry taught you alone.

AB. Off-label use is described in the chapter as "real, common, sometimes appropriate, and outside the label by definition." Explain how you would record an off-label use in a dossier without letting it blur into the Field 7 entry.

Part 5 — Synthesis and argument

AC. The chapter's central claim is that peptides have been standard oncology care for decades and almost nobody knows it. Write a 250-word explanation of that claim for a reader who has heard only that peptides are a wellness trend. Do not use the word frontier.

AD. † §27.8 argues that no approved oncology peptide broadly "supports," "modulates," or "optimizes" a healthy system. Attempt to find a counterexample. If you cannot find one, describe what you searched for and what the absence of a hit suggests. If you think you have found one, state its approved indication verbatim and check whether it survives the test.

AE. † Relugolix is oral because it is not a peptide. Write a short argument, addressed to a reader of Chapter 1, for why that single fact is more instructive about peptide pharmacology than any number of statements about what peptides can do.

AF. Someone you care about has been prescribed androgen deprivation therapy and asks whether the side effects are worth it. Without giving medical advice, write what you would say — including how you would explain that "compared to what?" is not an evasion of the question but the beginning of an answer. Then note which sentence in your draft you are least sure of, and why.